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 potassium channels in regulating interneuron excitability using high-resolution whole-cell patch clamp recording techniques in brain slices and organotypic hippocampal cultures. Specifically, we have demonstrated differential mechanisms of short and long-term plasticity, frequency dependent transmission, regulation of transmission by presynaptic metabotropic glutamate receptors and an interaction between short and long term changes in transmission at mossy fiber-interneuron and -pyramidal cell targets. Differential mechanisms of synaptic transmission between connected pairs of pyramidal neurons of the auditory cortex was also studied. We have also identified a subpopulation of inhibitory interneuron within the hilar/CA3 hippocampal subfields that is a target for histaminergic (H2) receptor modulation via PKA-phosphorylation of intrinsic voltage-dependent potassium channels formed by Kv3.2 subunits. Kv3.2 subunits endow interneurons with a fast-spiking phenotype. When PKA phosphorylated currents through Kv3.2 containing channels are blocked and interneuron action potential generation is shifted to a low frequency firing mode, which impacts not only interneuron function but the generation of coherent oscillations within the hippocampal principal cell populations. Modulation of gamma-frequency oscillations by muscarinic receptor activation in both wildtype and selective muscarine receptor knockouts was also studied.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst/Child Hlth/Human Dev
Department
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DUNS #
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Country
United States
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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
Pelkey, Kenneth A; McBain, Chris J (2007) Differential regulation at functionally divergent release sites along a common axon. Curr Opin Neurobiol 17:366-73
Isaac, John T R; Ashby, Michael; McBain, Chris J (2007) The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54:859-71
Ho, Michelle T-W; Pelkey, Kenneth A; Topolnik, Lisa et al. (2007) Developmental expression of Ca2+-permeable AMPA receptors underlies depolarization-induced long-term depression at mossy fiber CA3 pyramid synapses. J Neurosci 27:11651-62
Pelkey, Kenneth A; Yuan, Xiaoqing; Lavezzari, Gabriela et al. (2007) mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 52:108-17
Plant, Karen; Pelkey, Kenneth A; Bortolotto, Zuner A et al. (2006) Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat Neurosci 9:602-4
Torborg, Christine L; Berg, Allison P; Jeffries, Brian W et al. (2006) TASK-like conductances are present within hippocampal CA1 stratum oriens interneuron subpopulations. J Neurosci 26:7362-7
McBain, Chris J; Traynelis, Stephen F (2006) Malevolent lurkers no more: NMDA receptors come of age. J Physiol 575:317-8
Lawrence, J Josh; Saraga, Fernanda; Churchill, Joseph F et al. (2006) Somatodendritic Kv7/KCNQ/M channels control interspike interval in hippocampal interneurons. J Neurosci 26:12325-38
Pelkey, Kenneth A; Topolnik, Lisa; Lacaille, Jean-Claude et al. (2006) Compartmentalized Ca(2+) channel regulation at divergent mossy-fiber release sites underlies target cell-dependent plasticity. Neuron 52:497-510

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