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. In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, MF synapses onto CA3 pyramidal cells provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrated in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitated to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input could facilitate or depress in response to short trains of activity. CA3-tetanus toxin transgenic mice, which lack the capability of activating the feedback inhibitory loop, continued to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition was not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABAA receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings. Modulation of transmitter release from CCK-containing inhibitory interneurons Neurotransmitter release at most central synapses is synchronized to the timing of presynaptic action potentials. We demonstrated that three classes of cholecystokinin (CCK)-containing hippocampal interneurons show highly asynchronous release in response to trains of action potentials. This asynchrony was correlated to the class of presynaptic interneuron but was unrelated to their postsynaptic cell target. Asynchronous and synchronous release from CCK-containing interneurons showed different calcium dependences, such that the proportion of asynchronous release increased with external calcium concentration, suggesting that the modes of release are mediated by different calcium sensors. Asynchronous IPSCs include very large (up to 500 pA/7nS) amplitude events, which persist in low extracellular calcium and strontium, showing that they result from quantal transmitter release at single release sites. Finally, we demonstrated that asynchronous release was prominent in response to trains of presynaptic spikes that mimiced the natural activity of CCK-containing interneurons. That asynchronous release from CCK-containing interneurons is a widespread phenomenon indicates a role for these cells within the hippocampal network distinct from the phasic inhibition provided by parvalbumin-containing interneurons. The spatiotemporal origins of hippocampal interneuron diversity Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors. However, while studies of the early specification of neocortical interneurons are rapidly advancing, much to our surprise similar lineage analyses of hippocampal interneurons have lagged. We investigated the spatiotemporal origins of hippocampal interneurons using transgenic mice that specifically reported MGE- and CGE-derived interneurons either constitutively or inducibly. We found that hippocampal interneurons are produced in two neurogenic waves between E9-E12 and E12-E16 from MGE and CGE, respectively. These cells migrate through the marginal zone and subventricular zone to populated the stratum lacunosum moleculare prior to their final destination within the hippocampus proper. Migration from the MGE and CGE into the hippocampus takes varying amounts of time with cells born at later embryonic stages taking less time despite the increased dimensions of the migratory path length. In the mature hippocampus, CGE-derived interneurons primarily localize to superficial layers in strata lacunosum moleculare and deep radiatum, while MGE-derived interneurons readily populate all layers with preference for strata pyramidale and oriens. Combined molecular, anatomical, and electrophysiological interrogation of MGE/CGE-derived interneurons revealed that the MGE produces parvalbumin-, somatostatin-, and nitric oxide synthase-expressing interneurons including fast-spiking basket, bistratified, axo-axonic, oriens-lacunosum moleculare, neurogliaform, and ivy cells. In contrast, CGE-derived interneurons contain cholecystokinin, calretinin, vasoactive intestinal peptide, and reelin including non-fast-spiking basket, Schaffer collateral-associated, mossy fiber-associated, trilaminar, and additional neurogliaform cells. Our findings provide a basic blueprint of the developmental origins of hippocampal interneuron diversity.

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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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