Dr McBain's lab continues to investigate the differential mechanisms underlying synaptic transmission and plasticity onto both principal neurons and inhibitory interneurons within the hippocampal formation of the mammalian cortex. To this end we have established novel roles for both ionotropic and metabotropic glutamte receptors. Furthermore we have explored the role of intrinsic voltage-gated channels in regulating individual neuronal- and network-excitability with the use of high-resolution whole-cell patch clamp recording techniques in brain slices of hippocampus. We have also explored the neurogenesis, migration and development of specific cohorts of local circuit GABAergic interneurons arising from the ganglionic eminences. Cells originating from the medial ganglionic eminence give rise to distinct populations of interneurons that then migrate to and 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. We continue to explore novel forms of long lasting synaptic and cellular 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. Previously we have shown that the dentate gyrus 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. In this cycle we have completed the most detailed analysis to the roles played by inhibitory interneurons within the feedforward and feedback inhibitory circuits across a wide developmental age range. Our data suggest that a fine balance between GABAergic feedforward and feedback inhibitory systems maintains a narrow temporal window for glutamatergic derived excitation for CA3 principal cells. We have established an essential role for mGluR7b, a presynaptically located metabotropic glutamate receptor in controlling bidirectional synaptic plasticity at Ca-permeable AMPA receptors on hippocampal stratum lucidum 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 by triggering a nascent cAMP dependent pathway typically 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. We also identify 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. Our recent completed study indicates that burst firing activity in the mossy fiber-CA3 pathway serves as an essential trigger for the induction of long term depression and the conversion of immature synapses to mature synapsescomprised solely of Ca-impermeable AMPA receptors. 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.

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Li, Jun; Han, Wenyan; Pelkey, Kenneth A et al. (2017) Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development. Neuron 96:808-826.e8
Wyeth, Megan S; Pelkey, Kenneth A; Yuan, Xiaoqing et al. (2017) Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition. Cell Rep 20:2156-2168
Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:
Pelkey, Kenneth A; Chittajallu, Ramesh; Craig, Michael T et al. (2017) Hippocampal GABAergic Inhibitory Interneurons. Physiol Rev 97:1619-1747
Chittajallu, R; Wester, J C; Craig, M T et al. (2017) Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells. Nat Commun 8:152
Vargish, G A; Pelkey, K A; Yuan, X et al. (2017) Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol Psychiatry 22:56-67
Calvigioni, Daniela; Máté, Zoltán; Fuzik, János et al. (2017) Functional Differentiation of Cholecystokinin-Containing Interneurons Destined for the Cerebral Cortex. Cereb Cortex 27:2453-2468
Akgül, Gülcan; McBain, Chris J (2016) Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain. J Physiol 594:5471-90
Perszyk, Riley E; DiRaddo, John O; Strong, Katie L et al. (2016) GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity. Mol Pharmacol 90:689-702
Wester, Jason C; McBain, Chris J (2016) Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage. J Neurosci 36:2646-62

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