Cellular And Synaptic Physiology Of Hippocampal Interneurons

Child Health And Human Development

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Abstract

Over the last year Dr McBains lab has investigated differential mechanisms of synaptic transmission onto both hippocampal principal neurons and inhibitory interneurons. In addition we have explored the role of intrinsic voltage-gated channels in regulating neuron and network excitability using high-resolution whole-cell patch clamp recording techniques in brain slices of hippocampus. Specifically we have explored two novel forms of interneuron-long term depression of excitatory synaptic transmission between dentate gyrus granule cells and interneurons of the stratum lucidum that require calcium permeation through either Ca-permeable AMPA receptors or NMDA receptors for their induction. Evidence is emerging to suggest that the mossy fiber-CA3 system engages their interneuron targets via two parallel systems that differentially utilize NMDA receptors to endow distinct firing characteristics on their postsynaptic targets. In addition we have demonstrated an 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 mechansim of this long lasting potentiation which results from a nascent cAMP dependnet pathway that is sequestered when mGluR7 is present on the presynaptic surface membrane. Internalization of the metabotropic glutamate receptor allows a cAMP-dependent cascade to strengthen synaptic transmission on stratum lucidum interneurons. [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 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.