Cellular And Synaptic Physiology Of Hippocampal Interneurons

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Over the last year Dr McBains lab has continued their investigation into the differential mechanisms of synaptic transmission and plasticity onto both principal neurons and inhibitory interneurons within the hippocampal formation of the mammalian cortex. In addition to this main goal we have also explored the role of intrinsic voltage-gated channels in regulating individual neuron as well as network excitability with the use of high-resolution whole-cell patch clamp recording techniques in brain slices of hippocampus. A new research endeavor explores the neurogenesis, migration and development of specific cohorts of local circuit GABAergic interneurons arising from the medial ganglionic eminence. Cells originating from the MGE give rise to distinct populations of interneurons that then populate the developing hippocampus. For all of these studies we use a combinaiton of high resolution electrophysiological tools, molecular and biochemical techniques as well as confocal and two-photon imaging. [unreadable] We have continued to explore the novel forms of long lasting plasticity (both long term depression and long lasting potentiation) observed at glutamatergic excitatory synaptic connections between dentate gyrus granule cells and interneurons of the CA3 hippocampus. In this cycle we have provided evidence demonstrating that the mossy fiber-CA3 system engages their interneuron targets via multiple parallel systems that differentially utilize glutamate receptors to endow distinct synaptic properties and computational outcomes for the postsynaptic target neurons. We are currently exploring the roles played by both feedforward and feedback inhibitory circuits in sculpting the overall CA3 network excitability and our data suggest that a fine balance between these two inhibitory systems maintains a narrow temporal window of excitation for CA3 principal cells. W have continued to explore the essential role for the presynaptically located metabotropic glutamate receptor, mGluR7, in controlling bidirectional synaptic plasticity at Ca-permeable AMPA receptors on hippocampal interneurons interneurons. Activation of mGluR7 by synaptically released glutamate triggers long term depression of synaptic transmission and subsequent internalization of the mGluR7 protein. This reduction of transmitter release is accompanied by a persistent depression of the voltage gated Ca transient. As a consequence, subsequent rounds of synaptic stimulation reverse or potentiate this synaptic depression providing a novel mechanism of bidirectional control at inhibitory neuron synapses. We have now elucidated the underlying mechanism of this long lasting potentiation, which results from a nascent cAMP dependent pathway that is sequestered when mGluR7 is present on the presynaptic surface membrane. Activity dependent internalization of this metabotropic glutamate receptor permits activation of a cAMP-dependent cascade which then acts to strengthen synaptic transmission on stratum lucidum interneurons by a mechanism involving an increase in transmitter release probability. During the course of this study we also identified a novel mechanism of long lasting plasticity at developing mossy fiber synapses onto CA3 pyramidal neurons. This previously unexplored form of plasticity mimics a naturally occurring developmental switch in the phenotype of glutamate receptor present at these synapses. Young, immature synapses typically signal via Ca-permeable, GluR2-lacking AMPA-preferring receptors, induction of this long lasting form of synaptic depression triggers a switch in the receptor type which is then replaced by GluR2-containing, Ca-impermeable AMPA receptors. [unreadable] In addition, we continue to explore the developmental profile of local circuit inhibitory interneurons both at the level of their GABAA receptor activity and their synaptic targeting within the hippocampal network. Using a combination of electrophysiology and neuronal modeling we have elucidated the role of muscarinic and kainate receptors in regulating synaptic transmission onto downstream partners as well as elucidating the roles played by these receptors in tuning interneuron firing preference with a particular attention to discreet interneuron subpopulations. Muscarinic receptors activate a number of intrinsic ion conductances; the interplay of these three conductances combine to tune the frequency response of the interneuron firing pattern toward specific frequency ranges.