Cellular And Synaptic Physiology Of Hippocampal Interneu

Child Health And Human Development

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Abstract

GABAergic inhibitory interneurons comprise a population of hippocampal cells whose high degree of anatomical and functional divergence make them suitable candidates for controlling the activity of large populations of principal neurons. GABAergic inhibitory interneurons play a major role in the synchronization of neuronal activity and are involved in the generation of large-scale network oscillations. Thus interneurons function as a clock; that dictates when principal cells fire during suprathreshold excitatory drive. Interneurons receive strong excitatory glutamatergic innervation via numerous anatomically distinct afferent projections and recent evidence has demonstrated that the molecular composition of both the AMPA-preferring class of glutamate receptors expressed at interneuron synapses are often distinct from those found at principal cell synapses. Furthermore, single inhibitory interneurons can synthesize distinct AMPA receptors with defined subunit composition and target them to synaptic domains innervated by different afferent inputs. Over the last year Dr McBains lab has investigated differential mechanisms of synaptic transmission onto hippocampal inhibitory interneurons and the role of intrinsic voltage-gated channels in regulating interneuron excitability using high-resolution whole-cell patch clamp recording techniques in brain slices of hippocampus. Specifically we have described 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. Moreover evidence is emerging that suggests 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 metabotropic glutamate receptor, mGluR7, in controlling bidirectional synaptic plasticity at Ca-permeable AMPA receptors on hippocampal interneurons interneurons. Activation of presynaptically located mGluR7 by synaptically released glutamate triggers long term depression of synaptic transmission and subsequent internalization of the mGluR7 protein. As a consequence, subsequent rounds of synaptic stimulation reverse this depression or potentiate synaptic transmission providing a novel mechanism of bidirectional control at inhibitory neuron synapses. In addition the role of muscarinic receptors in tuning interneuron firing preference has been explored. Muscarinic receptors activate a number of intrinsic ion conductances; the interplay of these three conductances combine to tunethe frequency response of the interneuron firing pattern toward the theta frequency range. Finally modulation of gamma-frequency oscillations by kainate receptor activation in both wildtype and selective kainate receptor knockouts was also studied.