@article {67822, title = {Bidirectional synaptic plasticity rapidly modifies hippocampal representations.}, journal = {eLife}, volume = {10}, year = {2021}, month = {2021 Dec 09}, abstract = {

Learning requires neural adaptations thought to be mediated by activity-dependent synaptic plasticity. A relatively non-standard form of synaptic plasticity driven by dendritic calcium spikes, or plateau potentials, has been reported to underlie place field formation in rodent hippocampal CA1 neurons. Here we found that this behavioral timescale synaptic plasticity (BTSP) can also reshape existing place fields via bidirectional synaptic weight changes that depend on the temporal proximity of plateau potentials to pre-existing place fields. When evoked near an existing place field, plateau potentials induced less synaptic potentiation and more depression, suggesting BTSP might depend inversely on postsynaptic activation. However, manipulations of place cell membrane potential and computational modeling indicated that this anti-correlation actually results from a dependence on current synaptic weight such that weak inputs potentiate and strong inputs depress. A network model implementing this bidirectional synaptic learning rule suggested that BTSP enables population activity, rather than pairwise neuronal correlations, to drive neural adaptations to experience.

}, issn = {2050-084X}, doi = {10.7554/eLife.73046}, author = {Milstein, Aaron D and Li, Yiding and Bittner, Katie C and Grienberger, Christine and Soltesz, Ivan and Magee, Jeffrey C and Romani, Sandro} } @article {65617, title = {Membrane potential dynamics underlying context-dependent sensory responses in the hippocampus.}, journal = {Nature Neuroscience}, volume = {23}, year = {2020}, month = {2020 Jul 1}, pages = {881-91}, abstract = {

As animals navigate, they must identify features within context. In the mammalian brain, the hippocampus has the ability to separately encode different environmental contexts, even when they share some prominent features. To do so, neurons respond to sensory features in a context-dependent manner; however, it is not known how this encoding emerges. To examine this, we performed electrical recordings in the hippocampus as mice navigated in two distinct virtual environments. In CA1, both synaptic input to single neurons and population activity strongly tracked visual cues in one environment, whereas responses were almost completely absent when the same cue was presented in a second environment. A very similar, highly context-dependent pattern of cue-driven spiking was also observed in CA3. These results indicate that CA1 inherits a complex spatial code from upstream regions, including CA3, that have already computed a context-dependent representation of environmental features.

}, issn = {1546-1726}, doi = {10.1038/s41593-020-0646-2}, author = {Zhao, Xinyu and Wang, Yingxue and Spruston, Nelson and Magee, Jeffrey C} } @article {49477, title = {Active dendritic integration and mixed neocortical network representations during an adaptive sensing behavior.}, journal = {Nature Neuroscience}, volume = {21}, year = {2018}, month = {2018 Oct 22}, pages = {1583-90}, abstract = {

Animals strategically scan the environment to form an accurate perception of their surroundings. Here we investigated the neuronal representations that mediate this behavior. Ca imaging and selective optogenetic manipulation during an active sensing task reveals that layer 5 pyramidal neurons in the vibrissae cortex produce a diverse and distributed representation that is required for mice to adapt their whisking motor strategy to changing sensory cues. The optogenetic perturbation degraded single-neuron selectivity and network population encoding through a selective inhibition of active dendritic integration. Together the data indicate that active dendritic integration in pyramidal neurons produces a nonlinearly mixed network representation of joint sensorimotor parameters that is used to transform sensory information into motor commands during adaptive behavior. The prevalence of the layer 5 cortical circuit motif suggests that this is a general circuit computation.

}, issn = {1546-1726}, doi = {10.1038/s41593-018-0254-6}, author = {Ranganathan, Gayathri N and Apostolides, Pierre F and Harnett, Mark T and Xu, Ning-long and Druckmann, Shaul and Magee, Jeffrey C} } @article {48785, title = {Behavioral time scale synaptic plasticity underlies CA1 place fields.}, journal = {Science (New York, N.Y.)}, volume = {357}, year = {2017}, month = {2017 Sep 08}, pages = {1033-1036}, abstract = {

Learning is primarily mediated by activity-dependent modifications of synaptic strength within neuronal circuits. We discovered that place fields in hippocampal area CA1 are produced by a synaptic potentiation notably different from Hebbian plasticity. Place fields could be produced in vivo in a single trial by potentiation of input that arrived seconds before and after complex spiking. The potentiated synaptic input was not initially coincident with action potentials or depolarization. This rule, named behavioral time scale synaptic plasticity, abruptly modifies inputs that were neither causal nor close in time to postsynaptic activation. In slices, five pairings of subthreshold presynaptic activity and calcium (Ca(2+)) plateau potentials produced a large potentiation with an asymmetric seconds-long time course. This plasticity efficiently stores entire behavioral sequences within synaptic weights to produce predictive place cell activity.

}, issn = {1095-9203}, doi = {10.1126/science.aan3846}, author = {Bittner, Katie C and Milstein, Aaron D and Grienberger, Christine and Romani, Sandro and Magee, Jeffrey C} } @article {48253, title = {Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells.}, journal = {Nature Neuroscience}, volume = {20}, year = {2017}, month = {2017 Jan 23}, pages = {417-26}, abstract = {

Place cells in the CA1 region of the hippocampus express location-specific firing despite receiving a steady barrage of heterogeneously tuned excitatory inputs that should compromise output dynamic range and timing. We examined the role of synaptic inhibition in countering the deleterious effects of off-target excitation. Intracellular recordings in behaving mice demonstrate that bimodal excitation drives place cells, while unimodal excitation drives weaker or no spatial tuning in interneurons. Optogenetic hyperpolarization of interneurons had spatially uniform effects on place cell membrane potential dynamics, substantially reducing spatial selectivity. These data and a computational model suggest that spatially uniform inhibitory conductance enhances rate coding in place cells by suppressing out-of-field excitation and by limiting dendritic amplification. Similarly, we observed that inhibitory suppression of phasic noise generated by out-of-field excitation enhances temporal coding by expanding the range of theta phase precession. Thus, spatially uniform inhibition allows proficient and flexible coding in hippocampal CA1 by suppressing heterogeneously tuned excitation.

}, issn = {1546-1726}, doi = {10.1038/nn.4486}, author = {Grienberger, Christine and Milstein, Aaron D and Bittner, Katie C and Romani, Sandro and Magee, Jeffrey C} } @article {47300, title = {Axonal filtering allows reliable output during dendritic plateau-driven complex spiking in CA1 neurons.}, journal = {Neuron}, volume = {89}, year = {2016}, month = {2016 Feb 17}, pages = {770-783}, abstract = {

In CA1 pyramidal neurons, correlated inputs trigger dendritic plateau potentials that drive neuronal plasticity and firing rate modulation. Given the strong electrotonic coupling between soma and axon, the \>25\ mV depolarization associated with the plateau could propagate through the axon to influence action potential initiation, propagation, and neurotransmitter release. We examined this issue in brain slices, awake mice, and a computational model. Despite profoundly inactivating somatic and proximal axon Na(+) channels, plateaus evoked action potentials that recovered to full amplitude in the distal axon (\>150\ μm) and triggered neurotransmitter release similar to regular spiking. This effect was due to strong attenuation of plateau depolarizations by axonal K(+) channels, allowing full axon repolarization and Na(+) channel deinactivation. High-pass filtering of dendritic plateaus by axonal K(+) channels should thus enable accurate transmission of gain-modulated firing rates, allowing neuronal firing to be efficiently read out by downstream regions as a simple rate code.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.12.040}, author = {Apostolides, Pierre F and Milstein, Aaron D and Grienberger, Christine and Bittner, Katie C and Magee, Jeffrey C} } @article {46918, title = {Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons.}, journal = {Nature Neuroscience}, year = {2015}, month = {2015 Jul 13}, abstract = {

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.

}, issn = {1546-1726}, doi = {10.1038/nn.4062}, author = {Bittner, Katie C and Grienberger, Christine and Vaidya, Sachin P and Milstein, Aaron D and Macklin, John J and Suh, Junghyup and Tonegawa, Susumu and Magee, Jeffrey C} } @article {46184, title = {Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons.}, journal = {Journal of Neuroscience}, volume = {35}, year = {2015}, month = {2015 Jan 21}, pages = {1024-37}, abstract = {

The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.2813-14.2015}, author = {Harnett, Mark T and Magee, Jeffrey C and Williams, Stephen R} } @article {47087, title = {Inhibitory gating of input comparison in the CA1 microcircuit.}, journal = {Neuron}, volume = {87}, year = {2015}, month = {2015 Sep 23}, pages = {1274-89}, abstract = {

Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and\ feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.08.025}, author = {Milstein, Aaron D and Bloss, Erik B and Apostolides, Pierre F and Vaidya, Sachin P and Dilly, Geoffrey A and Zemelman, Boris V and Magee, Jeffrey C} } @article {6713, title = {Structured synaptic connectivity between hippocampal regions.}, journal = {Neuron}, volume = {81}, year = {2014}, month = {2014 Feb 5}, pages = {629-40}, abstract = {

The organization of synaptic connectivity within a neuronal circuit is a prime determinant of circuit function. We performed a comprehensive fine-scale circuit mapping of hippocampal regions (CA3-CA1) using the newly developed synapse labeling method, mGRASP. This mapping revealed spatially nonuniform and clustered synaptic connectivity patterns. Furthermore, synaptic clustering was enhanced between groups of neurons that shared a similar developmental/migration time window, suggesting a mechanism for establishing the spatial structure of synaptic connectivity. Such connectivity patterns are thought to effectively engage active dendritic processing and storage mechanisms, thereby potentially enhancing neuronal feature selectivity.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2013.11.026}, author = {Shaul Druckmann and Feng, Linqing and Lee, Bokyoung and Yook, Chaehyun and Zhao, Ting and Magee, Jeffrey C and Kim, Jinhyun} } @article {6267, title = {Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons.}, journal = {Neuron}, volume = {79}, year = {2013}, month = {2013 Aug 7}, pages = {516-29}, abstract = {

Active dendritic synaptic integration enhances the computational power of neurons. Such nonlinear processing generates an object-localization signal in the apical dendritic tuft of layer 5B cortical pyramidal neurons during sensory-motor behavior. Here, we employ electrophysiological and optical approaches in brain slices and behaving animals to investigate how excitatory synaptic input to this distal dendritic compartment influences neuronal output. We find that active dendritic integration throughout the apical dendritic tuft is highly compartmentalized by voltage-gated potassium (KV) channels. A high density of both transient and sustained KV channels was observed in all apical dendritic compartments. These channels potently regulated the interaction between apical dendritic tuft, trunk, and axosomatic integration zones to control neuronal output in\ vitro as well as the engagement of dendritic nonlinear processing in\ vivo during sensory-motor behavior. Thus, KV channels dynamically tune the interaction between active dendritic integration compartments in layer 5B pyramidal neurons to shape behaviorally relevant neuronal computations.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2013.06.005}, author = {Harnett, Mark T and Xu, Ning-long and Magee, Jeffrey C and Williams, Stephen R} } @article {6888, title = {Variable dendritic integration in hippocampal CA3 pyramidal neurons.}, journal = {Neuron}, volume = {80}, year = {2013}, month = {2013 Dec 18}, pages = {1438-50}, abstract = {

The hippocampal CA3 region is essential for pattern completion and generation of sharp-wave ripples. During these operations, coordinated activation of ensembles of CA3 pyramidal neurons produces spatiotemporally structured input patterns arriving onto dendrites of recurrently connected CA3 neurons. To understand how such input patterns are translated into specific output patterns, we characterized dendritic integration in CA3 pyramidal cells using two-photon imaging and glutamate uncaging. We found that thin dendrites of CA3 pyramidal neurons integrate synchronous synaptic input in a highly supralinear fashion. The amplification was primarily mediated by NMDA receptor activation and was present over a relatively broad range of spatiotemporal input patterns. The decay of voltage responses, temporal summation, and action potential output was regulated in a compartmentalized fashion mainly by a G-protein-activated inwardly rectifying K(+) current. Our results suggest that plastic dendritic integrative\ mechanisms may support ensemble behavior in pyramidal neurons of the hippocampal circuitry.

}, keywords = {Action Potentials, Animals, CA3 Region, Dendrites, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Glutamic Acid, Hippocampal, Male, N-Methylaspartate, Potassium Channels, Pyramidal Cells, Rats, Sodium}, issn = {1097-4199}, doi = {10.1016/j.neuron.2013.10.033}, author = {Makara, Judit K and Magee, Jeffrey C} } @article {5924, title = {Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition.}, journal = {Nature neuroscience}, volume = {15}, year = {2012}, month = {2012 May}, pages = {769-75}, abstract = {A consortium of inhibitory neurons control the firing patterns of pyramidal cells, but their specific roles in the behaving animal are largely unknown. We performed simultaneous physiological recordings and optogenetic silencing of either perisomatic (parvalbumin (PV) expressing) or dendrite-targeting (somatostatin (SOM) expressing) interneurons in hippocampal area CA1 of head-fixed mice actively moving a treadmill belt rich with visual-tactile stimuli. Silencing of either PV or SOM interneurons increased the firing rates of pyramidal cells selectively in their place fields, with PV and SOM interneurons having their largest effect during the rising and decaying parts of the place field, respectively. SOM interneuron silencing powerfully increased burst firing without altering the theta phase of spikes. In contrast, PV interneuron silencing had no effect on burst firing, but instead shifted the spikes{\textquoteright} theta phase toward the trough of theta. These findings indicate that perisomatic and dendritic inhibition have distinct roles in controlling the rate, burst and timing of hippocampal pyramidal cells.}, keywords = {Action Potentials, Animal, Animals, Behavior, Biophysics, Dendrites, Electric Stimulation, Exercise Test, Green Fluorescent Proteins, Halorhodopsins, Hippocampus, Humans, Inbred C57BL, Light, Mice, Movement, Neural Inhibition, Neurons, Optics and Photonics, Parvalbumins, Patch-Clamp Techniques, Photic Stimulation, Probability, Somatostatin, Spectrum Analysis, Time Factors, Time Perception, Touch, Transgenic}, issn = {1546-1726}, doi = {10.1038/nn.3077}, author = {Royer, S{\'e}bastien and Zemelman, Boris V and Losonczy, Attila and Kim, Jinhyun and Chance, Frances and Magee, Jeffrey C and Buzs{\'a}ki, Gy{\"o}rgy} } @article {5923, title = {Ion channel gradients in the apical tuft region of CA1 pyramidal neurons.}, journal = {PLoS one}, volume = {7}, year = {2012}, month = {2012}, pages = {e46652}, abstract = {

Dendritic ion channels play a critical role in shaping synaptic input and are fundamentally important for synaptic integration and plasticity. In the hippocampal region CA1, somato-dendritic gradients of AMPA receptors and the hyperpolarization-activated cation conductance (I(h)) counteract the effects of dendritic filtering on the amplitude, time-course, and temporal integration of distal Schaffer collateral (SC) synaptic inputs within stratum radiatum (SR). While ion channel gradients in CA1 distal apical trunk dendrites within SR have been well characterized, little is known about the patterns of ion channel expression in the distal apical tuft dendrites within stratum lacunosum moleculare (SLM) that receive distinct input from the entorhinal cortex via perforant path (PP) axons. Here, we measured local ion channels densities within these distal apical tuft dendrites to determine if the somato-dendritic gradients of I(h) and AMPA receptors extend into distal tuft dendrites. We also determined the densities of voltage-gated sodium channels and NMDA receptors. We found that the densities of AMPA receptors, I(h,) and voltage-gated sodium channels are similar in tuft dendrites in SLM when compared with distal apical dendrites in SR, while the ratio of NMDA receptors to AMPA receptors increases in tuft dendrites relative to distal apical dendrites within SR. These data indicate that the somato-dendritic gradients of I(h) and AMPA receptors in apical dendrites do not extend into the distal tuft, and the relative densities of voltage-gated sodium channels and NMDA receptors are poised to support nonlinear integration of correlated SC and PP input.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0046652}, author = {Bittner, Katie C and Andrasfalvy, Bertalan K and Magee, Jeffrey C} } @article {4487, title = {mGRASP enables mapping mammalian synaptic connectivity with light microscopy.}, journal = {Nature Methods}, volume = {9}, year = {2012}, month = {2012 Jan}, pages = {96-102}, abstract = {

The GFP reconstitution across synaptic partners (GRASP) technique, based on functional complementation between two nonfluorescent GFP fragments, can be used to detect the location of synapses quickly, accurately and with high spatial resolution. The method has been previously applied in the nematode and the fruit fly but requires substantial modification for use in the mammalian brain. We developed mammalian GRASP (mGRASP) by optimizing transmembrane split-GFP carriers for mammalian synapses. Using in silico protein design, we engineered chimeric synaptic mGRASP fragments that were efficiently delivered to synaptic locations and reconstituted GFP fluorescence in vivo. Furthermore, by integrating molecular and cellular approaches with a computational strategy for the three-dimensional reconstruction of neurons, we applied mGRASP to both long-range circuits and local microcircuits in the mouse hippocampus and thalamocortical regions, analyzing synaptic distribution in single neurons and in dendritic compartments.

}, issn = {1548-7105}, doi = {10.1038/nmeth.1784}, author = {Kim, Jinhyun and Zhao, Ting and Petralia, Ronald S and Yu, Yang and Peng, Hanchuan and Myers, Eugene and Magee, Jeffrey C} } @article {6294, title = {Nonlinear dendritic integration of sensory and motor input during an active sensing task.}, journal = {Nature}, volume = {492}, year = {2012}, month = {2012 Dec 13}, pages = {247-51}, abstract = {

Active dendrites provide neurons with powerful processing capabilities. However, little is known about the role of neuronal dendrites in behaviourally related circuit computations. Here we report that a novel global dendritic nonlinearity is involved in the integration of sensory and motor information within layer 5 pyramidal neurons during an active sensing behaviour. Layer 5 pyramidal neurons possess elaborate dendritic arborizations that receive functionally distinct inputs, each targeted to spatially separate regions. At the cellular level, coincident input from these segregated pathways initiates regenerative dendritic electrical events that produce bursts of action potential output and circuits featuring this powerful dendritic nonlinearity can implement computations based on input correlation. To examine this in vivo we recorded dendritic activity in layer 5 pyramidal neurons in the barrel cortex using two-photon calcium imaging in mice performing an object-localization task. Large-amplitude, global calcium signals were observed throughout the apical tuft dendrites when active touch occurred at particular object locations or whisker angles. Such global calcium signals are produced by dendritic plateau potentials that require both vibrissal sensory input and primary motor cortex activity. These data provide direct evidence of nonlinear dendritic processing of correlated sensory and motor information in the mammalian neocortex during active sensation.

}, keywords = {Animal, Animals, Behavior, Calcium, Dendrites, Inbred C57BL, Male, Mice, Motor Activity, Patch-Clamp Techniques, Pyramidal Cells, Sensation, Signal Transduction}, issn = {1476-4687}, doi = {10.1038/nature11601}, author = {Xu, Ning-long and Harnett, Mark T and Williams, Stephen R and Huber, Daniel and O{\textquoteright}Connor, Daniel H and Svoboda, Karel and Magee, Jeffrey C} } @article {5922, title = {Synaptic amplification by dendritic spines enhances input cooperativity.}, journal = {Nature}, volume = {491}, year = {2012}, month = {2012 Nov 22}, pages = {599-602}, abstract = {

Dendritic spines are the nearly ubiquitous site of excitatory synaptic input onto neurons and as such are critically positioned to influence diverse aspects of neuronal signalling. Decades of theoretical studies have proposed that spines may function as highly effective and modifiable chemical and electrical compartments that regulate synaptic efficacy, integration and plasticity. Experimental studies have confirmed activity-dependent structural dynamics and biochemical compartmentalization by spines. However, there is a longstanding debate over the influence of spines on the electrical aspects of synaptic transmission and dendritic operation. Here we measure the amplitude ratio of spine head to parent dendrite voltage across a range of dendritic compartments and calculate the associated spine neck resistance (R(neck)) for spines at apical trunk dendrites in rat hippocampal CA1 pyramidal neurons. We find that R(neck) is large enough (\ 500 MΩ) to amplify substantially the spine head depolarization associated with a unitary synaptic input by \ 1.5- to \ 45-fold, depending on parent dendritic impedance. A morphologically realistic compartmental model capable of reproducing the observed spatial profile of the amplitude ratio indicates that spines provide a consistently high-impedance input structure throughout the dendritic arborization. Finally, we demonstrate that the amplification produced by spines encourages electrical interaction among coactive inputs through an R(neck)-dependent increase in spine head voltage-gated conductance activation. We conclude that the electrical properties of spines promote nonlinear dendritic processing and associated forms of plasticity and storage, thus fundamentally enhancing the computational capabilities of neurons.

}, keywords = {Animals, Dendritic Spines, Electric Impedance, Excitatory Postsynaptic Potentials, Male, Models, Neurological, Pyramidal Cells, Rats, Sprague-Dawley, Synapses, Wistar}, issn = {1476-4687}, doi = {10.1038/nature11554}, author = {Harnett, Mark T and Makara, Judit K and Spruston, Nelson and Kath, William L and Magee, Jeffrey C} } @article {5295, title = {Observations on clustered synaptic plasticity and highly structured input patterns.}, journal = {Neuron}, volume = {72}, year = {2011}, month = {2011 Dec 22}, pages = {887-8}, abstract = {

In this issue of Neuron, Makino and Malinow and Kleindienst et\ al. present evidence of a behaviorally induced form of synaptic plasticity that would encourage the development of fine-scale structured input patterns and\ the binding of features within single neurons.

}, keywords = {Action Potentials, Animals, Cell Compartmentation, Dendrites, Female, Hippocampus, Neuronal Plasticity, Pregnancy, Sensory Deprivation, Synapses, Synaptic Transmission}, issn = {1097-4199}, doi = {10.1016/j.neuron.2011.12.009}, author = {Magee, Jeffrey C} } @article {2121, title = {Multi-array silicon probes with integrated optical fibers: light-assisted perturbation and recording of local neural circuits in the behaving animal.}, journal = {The European Journal of Neuroscience}, volume = {31}, year = {2010}, month = {2010 Jun}, pages = {2279-91}, abstract = {

Recordings of large neuronal ensembles and neural stimulation of high spatial and temporal precision are important requisites for studying the real-time dynamics of neural networks. Multiple-shank silicon probes enable large-scale monitoring of individual neurons. Optical stimulation of genetically targeted neurons expressing light-sensitive channels or other fast (milliseconds) actuators offers the means for controlled perturbation of local circuits. Here we describe a method to equip the shanks of silicon probes with micron-scale light guides for allowing the simultaneous use of the two approaches. We then show illustrative examples of how these compact hybrid electrodes can be used in probing local circuits in behaving rats and mice. A key advantage of these devices is the enhanced spatial precision of stimulation that is achieved by delivering light close to the recording sites of the probe. When paired with the expression of light-sensitive actuators within genetically specified neuronal populations, these devices allow the relatively straightforward and interpretable manipulation of network activity.

}, keywords = {Action Potentials, Animal, Animals, Behavior, Electric Stimulation, Electrophysiology, Light, Mice, Neurons, Neuropsychological Tests, Optical Fibers, Photic Stimulation, Rats, Recombinant Fusion Proteins, Silicon}, issn = {1460-9568}, doi = {10.1002/cbic.201000254}, author = {Royer, S{\'e}bastien and Zemelman, Boris V and Barbic, Mladen and Losonczy, Attila and Buzs{\'a}ki, Gy{\"o}rgy and Magee, Jeffrey C} } @article {3911, title = {Network mechanisms of theta related neuronal activity in hippocampal CA1 pyramidal neurons.}, journal = {Nature Neuroscience}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {967-72}, abstract = {

Although hippocampal theta oscillations represent a prime example of temporal coding in the mammalian brain, little is known about the specific biophysical mechanisms. Intracellular recordings support a particular abstract oscillatory interference model of hippocampal theta activity, the soma-dendrite interference model. To gain insight into the cellular and circuit level mechanisms of theta activity, we implemented a similar form of interference using the actual hippocampal network in mice in vitro. We found that pairing increasing levels of phasic dendritic excitation with phasic stimulation of perisomatic projecting inhibitory interneurons induced a somatic polarization and action potential timing profile that reproduced most common features. Alterations in the temporal profile of inhibition were required to fully capture all features. These data suggest that theta-related place cell activity is generated through an interaction between a phasic dendritic excitation and a phasic perisomatic shunting inhibition delivered by interneurons, a subset of which undergo activity-dependent presynaptic modulation.

}, keywords = {Animals, Gene Knock-In Techniques, Hippocampus, Inbred C57BL, Inhibitory Postsynaptic Potentials, Mice, Nerve Net, Organ Culture Techniques, Patch-Clamp Techniques, Pyramidal Cells, Theta Rhythm}, issn = {1546-1726}, doi = {10.1038/nn.2597}, author = {Losonczy, Attila and Zemelman, Boris V and Vaziri, Alipasha and Magee, Jeffrey C} } @article {2122, title = {Experience-dependent compartmentalized dendritic plasticity in rat hippocampal CA1 pyramidal neurons.}, journal = {Nature Neuroscience}, volume = {12}, year = {2009}, month = {2009 Dec}, pages = {1485-7}, abstract = {

The excitability of individual dendritic branches is a plastic property of neurons. We found that experience in an enriched environment increased propagation of dendritic Na(+) spikes in a subset of individual dendritic branches in rat hippocampal CA1 pyramidal neurons and that this effect was mainly mediated by localized downregulation of A-type K(+) channel function. Thus, dendritic plasticity might be used to store recent experience in individual branches of the dendritic arbor.

}, keywords = {Action Potentials, Animals, CA1 Region, Dendrites, Down-Regulation, Environment, Hippocampal, Memory, Neuronal Plasticity, Potassium Channels, Pyramidal Cells, Rats}, issn = {1546-1726}, doi = {10.1038/nn.2428}, author = {Makara, Judit K and Losonczy, Attila and Wen, Quan and Magee, Jeffrey C} } @article {3913, title = {Fast synaptic subcortical control of hippocampal circuits.}, journal = {Science}, volume = {326}, year = {2009}, month = {2009 Oct 16}, pages = {449-53}, abstract = {

Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

}, keywords = {Afferent, Animals, Electric Stimulation, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Inhibitory Postsynaptic Potentials, Interneurons, Mice, Neural Inhibition, Neural Pathways, Neurons, Patch-Clamp Techniques, Photic Stimulation, Raphe Nuclei, Rats, Serotonin, Sprague-Dawley, Synapses, Synaptic Potentials}, issn = {1095-9203}, doi = {10.1126/science.1178307}, author = {Varga, Viktor and Losonczy, Attila and Zemelman, Boris V and Borhegyi, Zsolt and Nyiri, G{\'a}bor and Domonkos, Andor and Hangya, Bal{\'a}zs and Holderith, No{\'e}mi and Magee, Jeffrey C and Freund, Tam{\'a}s F} } @article {3914, title = {Pathway interactions and synaptic plasticity in the dendritic tuft regions of CA1 pyramidal neurons.}, journal = {Neuron}, volume = {62}, year = {2009}, month = {2009 Apr 16}, pages = {102-11}, abstract = {

Input comparison is thought to occur in many neuronal circuits, including the hippocampus, where functionally important interactions between the Schaffer collateral and perforant pathways have been hypothesized. We investigated this idea using multisite, whole-cell recordings and Ca2+ imaging and found that properly timed, repetitive stimulation of both pathways results in the generation of large plateau potentials in distal dendrites of CA1 pyramidal neurons. These dendritic plateau potentials produce widespread Ca2+ influx, large after-depolarizations, burst firing output, and long-term potentiation of perforant path synapses. Plateau duration is directly related to the strength and temporal overlap of pathway activation and involves back-propagating action potentials and both NMDA receptors and voltage-gated Ca2+ channels. Thus, the occurrence of highly correlated SC and PP input to CA1 is signaled by a dramatic change in output mode and an increase in input efficacy, all induced by a large plateau potential in the distal dendrites of CA1 pyramidal neurons.

}, keywords = {Anesthetics, Animals, Biophysics, Calcium, Calcium Channel Blockers, Dendrites, Electric Stimulation, Excitatory Amino Acid Antagonists, Hippocampus, Inhibitory Postsynaptic Potentials, Local, Long-Term Potentiation, Membrane Potentials, Neural Pathways, Neuronal Plasticity, Newborn, Patch-Clamp Techniques, Pyramidal Cells, Rats, Spider Venoms, Sprague-Dawley, Synapses, Tetrodotoxin}, issn = {1097-4199}, doi = {10.1016/j.neuron.2009.03.007}, author = {Takahashi, Hiroto and Magee, Jeffrey C} } @article {3915, title = {Compartmentalized dendritic plasticity and input feature storage in neurons.}, journal = {Nature}, volume = {452}, year = {2008}, month = {2008 Mar 27}, pages = {436-41}, abstract = {

Although information storage in the central nervous system is thought to be primarily mediated by various forms of synaptic plasticity, other mechanisms, such as modifications in membrane excitability, are available. Local dendritic spikes are nonlinear voltage events that are initiated within dendritic branches by spatially clustered and temporally synchronous synaptic input. That local spikes selectively respond only to appropriately correlated input allows them to function as input feature detectors and potentially as powerful information storage mechanisms. However, it is currently unknown whether any effective form of local dendritic spike plasticity exists. Here we show that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-d-aspartate receptor (NMDAR)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggest that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatio-temporal correlation. We propose that this {\textquoteright}branch strength potentiation{\textquoteright} represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.

}, keywords = {Action Potentials, Animals, Cell Shape, Dendrites, Ion Channel Gating, Male, Mice, Models, N-Methyl-D-Aspartate, Neurological, Neuronal Plasticity, Pyramidal Cells, Rats, Receptors, Shal Potassium Channels, Sprague-Dawley}, issn = {1476-4687}, doi = {10.1038/nature06725}, author = {Losonczy, Attila and Makara, Judit K and Magee, Jeffrey C} } @article {2081, title = {High-speed, low-photodamage nonlinear imaging using passive pulse splitters. (With commentary)}, journal = {Nature Methods}, volume = {5}, year = {2008}, month = {2008 Feb}, pages = {197-202}, abstract = {

Pulsed lasers are key elements in nonlinear bioimaging techniques such as two-photon fluorescence excitation (TPE) microscopy. Typically, however, only a percent or less of the laser power available can be delivered to the sample before photoinduced damage becomes excessive. Here we describe a passive pulse splitter that converts each laser pulse into a fixed number of sub-pulses of equal energy. We applied the splitter to TPE imaging of fixed mouse brain slices labeled with GFP and show that, in different power regimes, the splitter can be used either to increase the signal rate more than 100-fold or to reduce the rate of photobleaching by over fourfold. In living specimens, the gains were even greater: a ninefold reduction in photobleaching during in vivo imaging of Caenorhabditis elegans larvae, and a six- to 20-fold decrease in the rate of photodamage during calcium imaging of rat hippocampal brain slices.

Commentary: Na Ji came to me early in her postdoc with an idea to reduce photodamage in nonlinear microscopy by splitting the pulses from an ultrafast laser into multiple subpulses of reduced energy. In six weeks, we constructed a prototype pulse splitter and obtained initial results confirming the validity of her vision. Further experiments with Jeff Magee demonstrated that the splitter could be used to increase imaging speed or reduce photodamage in two photon microscopy by one to two orders of magnitude. This project is a great example of how quickly one can react and exploit new ideas in the Janelia environment.

}, keywords = {Animals, Caenorhabditis elegans, Cell Survival, Cells, Cultured, Equipment Design, Equipment Failure Analysis, Fluorescence, Image Enhancement, Lasers, Light, Lighting, Mice, Microscopy, Nonlinear Dynamics, Rats}, issn = {1548-7105}, doi = {10.1038/nmeth.1175}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18204458}, author = {Ji, Na and Magee, Jeffrey C and Betzig, Eric} } @article {3916, title = {High-speed, low-photodamage nonlinear imaging using passive pulse splitters.}, journal = {Nature Methods}, volume = {5}, year = {2008}, month = {2008 Feb}, pages = {197-202}, abstract = {

Pulsed lasers are key elements in nonlinear bioimaging techniques such as two-photon fluorescence excitation (TPE) microscopy. Typically, however, only a percent or less of the laser power available can be delivered to the sample before photoinduced damage becomes excessive. Here we describe a passive pulse splitter that converts each laser pulse into a fixed number of sub-pulses of equal energy. We applied the splitter to TPE imaging of fixed mouse brain slices labeled with GFP and show that, in different power regimes, the splitter can be used either to increase the signal rate more than 100-fold or to reduce the rate of photobleaching by over fourfold. In living specimens, the gains were even greater: a ninefold reduction in photobleaching during in vivo imaging of Caenorhabditis elegans larvae, and a six- to 20-fold decrease in the rate of photodamage during calcium imaging of rat hippocampal brain slices.

}, keywords = {Animals, Caenorhabditis elegans, Cell Survival, Cells, Cultured, Equipment Design, Equipment Failure Analysis, Fluorescence, Image Enhancement, Lasers, Light, Lighting, Mice, Microscopy, Nonlinear Dynamics, Rats}, issn = {1548-7105}, doi = {10.1038/nmeth.1175}, author = {Ji, Na and Magee, Jeffrey C and Betzig, Eric} } @article {2126, title = {Associative pairing enhances action potential back-propagation in radial oblique branches of CA1 pyramidal neurons.}, journal = {The Journal of Physiology}, volume = {580}, year = {2007}, month = {2007 May 1}, pages = {787-800}, abstract = {

Back-propagating action potentials (bAPs) are involved in associative synaptic plasticity and the modulation of dendritic excitability. We have used high-speed confocal and two-photon imaging to measure calcium and voltage signals associated with action potential propagation into oblique branches of CA1 pyramidal neurons in adult hippocampal slices. The spatial profile of the bAP-associated Ca(2+) influx was biphasic, with an initial increase in the proximity of the branch point followed by a progressive decrease. Voltage imaging in the branches showed that bAP amplitude was initially constant and then steadily declined with distance from the soma. To determine the role of transient K(+) channels in this profile, we used external Ba(2+) (150 microm) as a channel blocker, after characterizing its effect on A-type K(+) channels in the apical trunk. Bath application of Ba(2+) significantly reduced the A-type K(+) current in outside-out patches and nearly eliminated the distance-dependent decrease in bAP amplitude and its associated Ca(2+) signal. Finally, small amplitude bAPs at more distal oblique branch locations could be boosted by simultaneous branch depolarization, such that the paired Ca(2+) signal became nearly the same for proximal and distal oblique dendrites. These data suggest that dendritic K(+) channels regulate the amplitude of bAPs to create a dendritic Ca(2+) signal whose magnitude is inversely related to the electrotonic distance from the soma when bAPs are not associated with a significant amount of localized synaptic input. This distance-dependent Ca(2+) signal from bAPs, however, can be amplified and a strong associative signal is produced once the proper correlation between synaptic activation and AP output is achieved. We hypothesize that these two signals may be involved in the regulation of the expression and activity of dendritic voltage- and ligand-gated ion channels.

}, keywords = {Action Potentials, Animals, Barium, Calcium, Dendrites, Hippocampus, Knockout, Male, Mice, Neuronal Plasticity, Potassium Channel Blockers, Potassium Channels, Pyramidal Cells, Rats, Sprague-Dawley, Synapses}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {Gasparini, Sonia and Losonczy, Attila and Chen, Xixi and Johnston, Daniel and Magee, Jeffrey C} } @article {3918, title = {Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons.}, journal = {Neuron}, volume = {50}, year = {2006}, month = {2006 Apr 20}, pages = {291-307}, abstract = {

Although radial oblique dendrites are a major synaptic input site in CA1 pyramidal neurons, little is known about their integrative properties. We have used multisite two-photon glutamate uncaging to deliver different spatiotemporal input patterns to single branches while simultaneously recording the uncaging-evoked excitatory postsynaptic potentials and local Ca2+ signals. Asynchronous input patterns sum linearly in spite of the spatial clustering and produce Ca2+ signals that are mediated by NMDA receptors (NMDARs). Appropriately timed and sized input patterns ( approximately 20 inputs within approximately 6 ms) produce a supralinear summation due to the initiation of a dendritic spike. The Ca2+ signals associated with synchronous input were larger and mediated by influx through both NMDARs and voltage-gated Ca2+ channels (VGCCs). The oblique spike is a fast Na+ spike whose duration is shaped by the coincident activation of NMDAR, VGCCs, and transient K+ currents. Our results suggest that individual branches can function as single integrative compartments.

}, keywords = {Animals, Calcium Channels, Dendrites, Excitatory Postsynaptic Potentials, Glutamic Acid, N-Methyl-D-Aspartate, Patch-Clamp Techniques, Pyramidal Cells, Rats, Receptors, Sprague-Dawley, Synapses, Synaptic Transmission}, issn = {0896-6273}, doi = {10.1016/j.neuron.2006.03.016}, author = {Losonczy, Attila and Magee, Jeffrey C} } @article {2130, title = {Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus.}, journal = {The Journal of Physiology}, volume = {570}, year = {2006}, month = {2006 Feb 1}, pages = {553-65}, abstract = {

Although the function of sleep remains elusive, there is compelling evidence to suggest that sleep plays an important role in learning and memory. A number of studies have now shown that sleep deprivation (SD) results in significant impairment of long-term potentiation (LTP) in the hippocampus. In this study, we have attempted to determine the mechanisms responsible for this impairment. After 72 h SD using the multiple-platform technique, we observed a reduction in the whole-cell recorded NMDA/AMPA ratio of CA1 pyramidal cells in response to Schaffer collateral stimulation. This impairment was specific to sleep deprivation as rats placed over a single large platform, which allowed sleep, had a normal NMDA/AMPA ratio. mEPSCs evoked by local application of a high osmolarity solution revealed no differences in the AMPA receptor function. NMDA currents recorded from outside-out patches excised from the distal dendrites of CA1 cells displayed a reduction in amplitude after SD. While there were no alterations in the glutamate sensitivity, channel open probability or the single channel conductance of the receptor, a crosslinking assay demonstrated that the NR1 and NR2A subunits of NMDA receptors were preferentially retained in the cytoplasm after SD, indicating that SD alters NMDAR surface expression. In summary, we have identified a potential mechanism underlying SD-induced LTP impairment. This synaptic alteration may underlie the cognitive deficits seen following sleep deprivation and could represent a target for future intervention studies.

}, keywords = {AMPA, Animals, Electric Stimulation, Excitatory Postsynaptic Potentials, Glutamic Acid, Glycine, Hippocampus, Ion Channel Gating, Kinetics, Long-Term Potentiation, Male, N-Methyl-D-Aspartate, Patch-Clamp Techniques, Rats, Receptors, Sleep Deprivation, Sprague-Dawley, Synaptic Transmission}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {McDermott, Carmel M and Hardy, Mattie N and Bazan, Nicolas G and Magee, Jeffrey C} } @article {2128, title = {State-dependent dendritic computation in hippocampal CA1 pyramidal neurons.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {26}, year = {2006}, month = {2006 Feb 15}, pages = {2088-100}, abstract = {

Depending on the behavioral state, hippocampal CA1 pyramidal neurons receive very distinct patterns of synaptic input and likewise produce very different output patterns. We have used simultaneous dendritic and somatic recordings and multisite glutamate uncaging to investigate the relationship between synaptic input pattern, the form of dendritic integration, and action potential output in CA1 neurons. We found that when synaptic input arrives asynchronously or highly distributed in space, the dendritic arbor performs a linear integration that allows the action potential rate and timing to vary as a function of the quantity of the input. In contrast, when synaptic input arrives synchronously and spatially clustered, the dendritic compartment receiving the clustered input produces a highly nonlinear integration that leads to an action potential output that is extraordinarily precise and invariant. We also present evidence that both of these forms of information processing may be independently engaged during the two distinct behavioral states of the hippocampus such that individual CA1 pyramidal neurons could perform two different state-dependent computations: input strength encoding during theta states and feature detection during sharp waves.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Animals, Dendrites, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Patch-Clamp Techniques, Pyramidal Cells, Rats, Sprague-Dawley, Synapses, Tetrodotoxin}, issn = {1529-2401}, doi = {10.1002/cbic.201000254}, author = {Gasparini, Sonia and Magee, Jeffrey C} } @article {2132, title = {Plasticity of dendritic function.}, journal = {Current Opinion in Neurobiology}, volume = {15}, year = {2005}, month = {2005 Jun}, pages = {334-42}, abstract = {

The various properties of neuronal dendrites{\textendash}their morphology, active membrane and synaptic properties{\textendash}all play important roles in determining the functional capabilities of central nervous system neurons. Because of their fundamental involvement in both synaptic integration and synaptic plasticity, the active dendritic properties are important for both neuronal information processing and storage. The active properties of dendrites are determined by the densities of voltage-gated ion channels located within the dendrites in addition to the biophysical characteristics of those channels. The real power of this system resides in the level of plasticity that is provided by the many forms of channel modulation known to exist in neurons. Indeed, voltage gated ion channel modulation shapes the active properties of neuronal dendrites to specific conditions, thus tailoring the functional role of the single neuron within its circuit.

}, keywords = {Action Potentials, Brain, Dendrites, Ion Channel Gating, Ion Channels, Neuronal Plasticity}, issn = {0959-4388}, doi = {10.1002/cbic.201000254}, author = {Magee, Jeffrey C and Johnston, Daniel} } @article {2134, title = {Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurones.}, journal = {The Journal of Physiology}, volume = {559}, year = {2004}, month = {2004 Sep 1}, pages = {543-54}, abstract = {

In the CA1 region of the hippocampus, LTP is thought to be initiated by a transient activation of NMDA receptors and is expressed as a persistent increase in synaptic transmission through AMPA receptors. To investigate the postsynaptic modifications of AMPA receptors involved in this enhanced synaptic transmission, the channel density and single-channel properties of extrasynaptic AMPA receptors located in synaptically active dendritic regions were examined following the induction of LTP. Following tetanic stimulation an outside-out patch was excised from the apical dendrite near the point of stimulation and saturating concentrations of glutamate were rapidly applied to the patch. AMPA current amplitude and duration were increased significantly in patches pulled from dendrites that expressed LTP. Non-stationary fluctuation analysis of AMPA currents indicated that AMPA channel number was nearly twofold larger than in controls, while single channel conductance and maximum open-probability were unchanged. Furthermore, while subtle changes in AMPA channel kinetics could also be observed, we did not find any evidence that receptor affinity or rectification properties were altered by LTP induction. Very similar results were found when CaMK-II activity was increased through the intracellular application of Ca/CaM. Together, we interpret our data to indicate that the stimuli used here produce an increased delivery of AMPA receptors to synaptically active regions of the apical dendrite without inducing any significant changes in their basic biophysical properties and that such delivery is a key element in this form of synaptic plasticity.

}, keywords = {AMPA, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Glutamic Acid, Long-Term Potentiation, Pyramidal Cells, Rats, Receptors, Sprague-Dawley}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {Andrasfalvy, Bertalan K and Magee, Jeffrey C} } @article {2133, title = {On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {24}, year = {2004}, month = {2004 Dec 8}, pages = {11046-56}, abstract = {

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: approximately 50 synaptic inputs spread over 100 mum of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [-48 +/- 1 mV (n = 30) vs -56 +/- 1 mV (n = 7), respectively] and are mainly generated and shaped by dendritic Na+ and K+ currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in the V(m) and the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

}, keywords = {Action Potentials, AMPA, Animals, Dendrites, Electrodes, Excitatory Postsynaptic Potentials, Ion Channels, Models, N-Methyl-D-Aspartate, Neurological, Pyramidal Cells, Rats, Receptors, Sprague-Dawley}, issn = {1529-2401}, doi = {10.1002/cbic.201000254}, author = {Gasparini, Sonia and Migliore, Michele and Magee, Jeffrey C} } @article {2137, title = {Impaired regulation of synaptic strength in hippocampal neurons from GluR1-deficient mice.}, journal = {The Journal of Physiology}, volume = {552}, year = {2003}, month = {2003 Oct 1}, pages = {35-45}, abstract = {

Neurons of the central nervous system (CNS) exhibit a variety of forms of synaptic plasticity, including associative long-term potentiation and depression (LTP/D), homeostatic activity-dependent scaling and distance-dependent scaling. Regulation of synaptic neurotransmitter receptors is currently thought to be a common mechanism amongst many of these forms of plasticity. In fact, glutamate receptor 1 (GluR1 or GluRA) subunits containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors have been shown to be required for several forms of hippocampal LTP and a particular hippocampal-dependent learning task. Because of this importance in associative plasticity, we sought to examine the role of these receptors in other forms of synaptic plasticity in the hippocampus. To do so, we recorded from the apical dendrites of hippocampal CA1 pyramidal neurons in mice lacking the GluR1 subunit (GluR1 -/-). Here we report data from outside-out patches that indicate GluR1-containing receptors are essential to the extrasynaptic population of AMPA receptors, as this pool was nearly empty in the GluR1 -/- mice. Additionally, these receptors appear to be a significant component of the synaptic glutamate receptor pool because the amplitude of spontaneous synaptic currents recorded at the site of input and synaptic AMPA receptor currents evoked by focal glutamate uncaging were both substantially reduced in these mice. Interestingly, the impact on synaptic weight was greatest at distant synapses such that the normal distance-dependent synaptic scaling used by these cells to counter dendritic attenuation was lacking in GluR1 -/- mice. Together the data suggest that the highly regulated movement of GluR1-containing AMPA receptors between extrasynaptic and synaptic receptor pools is critically involved in establishing two functionally diverse forms of synaptic plasticity: LTP and distance-dependent scaling.

}, keywords = {AMPA, Animals, Hippocampus, Inbred C57BL, Kinetics, Long-Term Potentiation, Mice, Mutant Strains, Neuronal Plasticity, Patch-Clamp Techniques, Pyramidal Cells, Receptors, Synapses}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {Andrasfalvy, Bertalan K and Smith, Mark A and Borchardt, Thilo and Sprengel, Rolf and Magee, Jeffrey C} } @article {2140, title = {Mechanism of the distance-dependent scaling of Schaffer collateral synapses in rat CA1 pyramidal neurons.}, journal = {The Journal of Physiology}, volume = {548}, year = {2003}, month = {2003 Apr 1}, pages = {245-58}, abstract = {

Schaffer collateral axons form excitatory synapses that are distributed across much of the dendritic arborization of hippocampal CA1 pyramidal neurons. Remarkably, AMPA-receptor-mediated miniature EPSP amplitudes at the soma are relatively independent of synapse location, despite widely different degrees of dendritic filtering. A progressive increase with distance in synaptic conductance is thought to produce this amplitude normalization. In this study we examined the mechanism(s) responsible for spatial scaling by making whole-cell recordings from the apical dendrites of CA1 pyramidal neurons. We found no evidence to suggest that there is any location dependence to the range of cleft glutamate concentrations found at Schaffer collateral synapses. Furthermore, we observed that release probability (Pr), paired-pulse facilitation and the size of the readily releasable vesicular pool are not dependent on synapse location. Thus, there do not appear to be any changes in the fundamental presynaptic properties of Schaffer collateral synapses that could account for distance-dependent scaling. On the other hand, two-photon uncaging of 4-methoxy-7-nitroindolinyl-caged L-glutamate onto isolated dendritic spines shows that the number of postsynaptic AMPA receptors per spine increases with distance from the soma. We conclude, therefore, that the main synaptic mechanism involved in the production of distance-dependent scaling of Schaffer collateral synapses is an elevated postsynaptic AMPA receptor density.

}, keywords = {Algorithms, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, AMPA, Animals, Computer Simulation, Dendrites, Electrophysiology, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Glutamates, Glutamic Acid, Hippocampus, Indoles, Kinetics, Kynurenic Acid, N-Methyl-D-Aspartate, Neurotransmitter Agents, Patch-Clamp Techniques, Pyramidal Cells, Rats, Receptors, Sprague-Dawley, Synapses, Tetrodotoxin}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {Smith, Mark A and Ellis-Davies, Graham C R and Magee, Jeffrey C} } @article {2141, title = {A prominent role for intrinsic neuronal properties in temporal coding.}, journal = {Trends in Neurosciences}, volume = {26}, year = {2003}, month = {2003 Jan}, pages = {14-6}, abstract = {

A recent report presents evidence that the exact timing of action potential output in rat hippocampal pyramidal neurons is similarly modulated during several diverse forms of behavior. These data suggest that it is, to a large degree, the intrinsic properties of the neurons themselves that produce this temporal coding of information. Thus, this report provides an outstanding example of the importance of single neuronal properties, even during complex behaviors.

}, keywords = {Animals, Automatic Data Processing, Hippocampus, Interneurons, Membrane Potentials, Neurons, Rats, Theta Rhythm, Time Factors}, issn = {0166-2236}, doi = {10.1002/cbic.201000254}, author = {Magee, Jeffrey C} } @article {2136, title = {Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {23}, year = {2003}, month = {2003 Oct 22}, pages = {9687-95}, abstract = {

Although the function of sleep remains elusive, several lines of evidence suggest that sleep has an important role in learning and memory. In light of the available data and with the prevalence of sleep deprivation (SD), we sought to determine the effect of SD on neuronal functioning. We found that the exposure of rats to 72 hr of primarily rapid eye movement SD impaired their subsequent performance on a hippocampus-dependent spatial learning task but had no effect on an amygdala-dependent learning task. To determine the underlying cellular level mechanisms of this hippocampal deficit, we examined the impact of SD on several fundamental aspects of membrane excitability and synaptic physiology in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. We found that neuronal excitability was severely reduced in CA1 neurons but not in granule cells and that the production of long-term potentiation of synaptic strength was inhibited in both areas. Using multiple SD methods we further attempted to differentiate the effects of sleep deprivation from those associated with the nonspecific stress induced by the sleep deprivation methods. Together these data suggest that failure to acquire adequate sleep produces several molecular and cellular level alterations that profoundly inhibit hippocampal functioning.

}, keywords = {Amygdala, Animal, Animals, Behavior, Cell Membrane, Cues, Electroencephalography, Excitatory Postsynaptic Potentials, Hippocampus, Long-Term Potentiation, Long-Term Synaptic Depression, Male, Memory, Neuronal Plasticity, Neurons, Physiological, Pyramidal Cells, Rats, Sleep Deprivation, Sprague-Dawley, Stress, Synapses}, issn = {1529-2401}, doi = {10.1002/cbic.201000254}, author = {McDermott, Carmel M and LaHoste, Gerald J and Chen, Chu and Musto, Alberto and Bazan, Nicolas G and Magee, Jeffrey C} } @article {2142, title = {Phosphorylation-dependent differences in the activation properties of distal and proximal dendritic Na+ channels in rat CA1 hippocampal neurons.}, journal = {The Journal of Physiology}, volume = {541}, year = {2002}, month = {2002 Jun 15}, pages = {665-72}, abstract = {

{At distal dendritic locations, the threshold for action potential generation is higher and the amplitude of back-propagating spikes is decreased. To study whether these characteristics depend upon Na+ channels, their voltage-dependent properties at proximal and distal dendritic locations were compared in CA1 hippocampal neurons. Distal Na+ channels activated at more hyperpolarized voltages than proximal (half-activation voltages were -20.4 +/- 2.4 mV vs. -12.0 +/- 1.7 mV for distal and proximal patches, respectively

}, keywords = {Algorithms, Animals, Axons, Dendrites, Electrophysiology, Enzyme Inhibitors, Hippocampus, Membrane Potentials, Neurons, Patch-Clamp Techniques, Phosphorylation, Protein Kinase Inhibitors, Rats, Sodium Channels, Sprague-Dawley, Staurosporine}, issn = {0022-3751}, doi = {10.1002/cbic.201000254}, author = {Gasparini, Sonia and Magee, Jeffrey C} }