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. 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. We have continued to explore the role of adult born granule cells within the dentate gyrus formation. Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we collaborated with the lab of Dr Tonegawa at MIT/RIKEN who created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2012
Total Cost
$1,667,918
Indirect Cost
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State
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Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:
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
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
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
Pelkey, Kenneth A; Barksdale, Elizabeth; Craig, Michael T et al. (2016) Pentraxins Coordinate Excitatory Synapse Maturation and Circuit Integration of Parvalbumin Interneurons. Neuron 90:661
Pelkey, Kenneth A; Barksdale, Elizabeth; Craig, Michael T et al. (2015) Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 85:1257-72
Craig, Michael T; McBain, Chris J (2015) Fast gamma oscillations are generated intrinsically in CA1 without the involvement of fast-spiking basket cells. J Neurosci 35:3616-24

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