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, genetic, 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 continue to investigate 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. Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors. MGE-derived interneuron synapses were dominated by GluA2-lacking AMPA-type glutamate receptors (AMPARs), with little contribution from NMDA-type receptors (NMDARs) throughout development. In contrast, CGE-derived cell synapses had large NMDAR components and used GluA2-containing AMPARs. In neonates, both MGE- and CGE-derived interneurons expressed primarily GluN2B subunit-containing NMDARs, which most CGE-derived interneurons retained into adulthood. However, MGE-derived interneuron NMDARs underwent a GluN2B-to-GluN2A switch that could be triggered acutely with repetitive synaptic activity. Our findings establish ganglionic eminence-dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells. 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. In the developing nervous system synaptic refinement, typified by the neuromuscular junction where supernumerary connections are eliminated by axon retraction leaving the postsynaptic target innervated by a single dominant input, critically regulates neuronal circuit formation. Whether such competition-based pruning continues in established circuits of mature animals remains unknown. This question is particularly relevant in the context of adult neurogenesis where newborn cells must integrate into preexisting circuits, and thus, potentially compete with functionally mature synapses to gain access to their postsynaptic targets. The hippocampus plays an important role in memory formation/retrieval and the dentate gyrus (DG) subfield exhibits continued neurogenesis into adulthood. Therefore, this region contains both mature granule cells (old GCs) and immature recently born GCs that are generated throughout adult life (young GCs), providing a neurogenic niche model to examine the role of competition in synaptic refinement. Recent work from an independent group in developing animals indicated that embryonically/early postnatal generated GCs placed at a competitive disadvantage by selective expression of tetanus toxin (TeTX) to prevent synaptic release rapidly retracted their axons, and that this retraction was driven by competition from newborn GCs lacking TeTX. In contrast, following 3-6 months of selective TeTX expression in old GCs of adult mice we did not observe any evidence of axon retraction. Indeed ultrastructural analyses indicated that the terminals of silenced GCs even maintained synaptic contact with their postsynaptic targets. Furthermore, we did not detect any significant differences in the electrophysiological properties between old GCs in control and TeTX conditions. Thus, our data demonstrate a remarkable stability in the face of a relatively prolonged period of altered synaptic competition between two populations of neurons within the adult brain.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2013
Total Cost
$2,147,151
Indirect Cost
City
State
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Johnston, April; McBain, Chris J; Fisahn, Andre (2014) 5-HT1A Receptor-Activation Hyperpolarizes Pyramidal Cells and Suppresses Hippocampal Gamma Oscillations via Kir3 Channel-Activation. J Physiol :
Wyeth, Megan S; Pelkey, Kenneth A; Petralia, Ronald S et al. (2014) Neto auxiliary protein interactions regulate kainate and NMDA receptor subunit localization at mossy fiber-CA3 pyramidal cell synapses. J Neurosci 34:622-8
Wester, Jason C; McBain, Chris J (2014) Behavioral state-dependent modulation of distinct interneuron subtypes and consequences for circuit function. Curr Opin Neurobiol 29:118-25
Matta, Jose A; Pelkey, Kenneth A; Craig, Michael T et al. (2013) Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat Neurosci 16:1032-41
Craig, Michael T; Mayne, Elizabeth W; Bettler, Bernhard et al. (2013) Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity. J Physiol 591:835-43
Ho, T M; Pelkey, K A; Pelletier, J G et al. (2009) Burst firing induces postsynaptic LTD at developing mossy fibre-CA3 pyramid synapses. J Physiol 587:4441-54
McBain, Chris J; Kauer, Julie A (2009) Presynaptic plasticity: targeted control of inhibitory networks. Curr Opin Neurobiol 19:254-62
Suh, Young Ho; Pelkey, Kenneth A; Lavezzari, Gabriela et al. (2008) Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7. Neuron 58:736-48
McBain, Chris J (2008) Differential mechanisms of transmission and plasticity at mossy fiber synapses. Prog Brain Res 169:225-40
Terashima, Akira; Pelkey, Kenneth A; Rah, Jong-Cheol et al. (2008) An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity. Neuron 57:872-82

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