Inhibitory interneurons in the hippocampus regulate pyramidal cells and prevent hyperexcitability that leads to epileptiform activity. Glutamatergic transmission onto interneurons activates these cells to drive these functions. Recently, it has been shown that hippocampal interneurons express the kainate subtype of ionotropic glutamate receptor, and these kainate receptors (KARs) are synaptically activated. Postsynaptic KARs on interneurons contribute to the excitatory postsynaptic potential (EPSP). KARs on interneurons also depress the release of GABA from interneurons onto pyramidal cells, although the mechanisms underlying this effect remain unclear. These two actions suggest that interneuronal KARs play a major role in the control of inhibitory activity and output in the hippocampus, and possibly represent a therapeutic target to limit hyperexcitability during epilepsy. However, at present it is not possible to critically evaluate this possibility, because insufficient information is available about the functions of interneuronal KARs, the mechanisms by which these functions can be regulated, or the mechanisms by which KARs regulate GABA release. This proposal will seek to address these gaps in our understanding of KARs on interneurons. Using whole-cell patch clamp techniques, the activity of KARs on interneurons will be recorded and manipulated using pharmacological tools.
Three specific aims will be addressed. (1) Functions for postsynaptic KARs will be identified, by testing four hypotheses: (a) that KARs are calcium-permeable and can initiate calcium-dependent signaling; (b) that KARs are segregated to different afferent pathways than AMPA receptors; (c) that KARs allow interneurons to perform temporal integration at low afferent firing frequencies; and (d) that these three functions are differentially distributed among different interneuronal subclasses. (2) Mechanisms of regulating the KAR-mediated EPSP will be identified, by testing two hypotheses: (a) that the KAR-mediated EPSP is regulated by continuous receptor delivery to, and removal from, the synapse; and (b) that the KAR-mediated EPSP is subject to activity-dependent synaptic plasticity. (3) Mechanisms underlying the presynaptic actions of interneuronal KARs will be identified, by testing two hypotheses: (a) that glutamate can activate presynaptic KARs that directly regulate GABA release; and (b) that the depression induced by KARs is an indirect consequence of interneuronal spiking. These experiments will provide information about the role of interneuronal KARs in the hippocampus, and provide a rational basis for future experiments to assess the possibility of manipulating these KARs to control hyperexcitability.
|Wondolowski, Joyce; Frerking, Matthew (2009) Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1. J Neurosci 29:563-74|
|Yang, Yunlei; Wang, Xiao-bin; Frerking, Matthew et al. (2008) Spine expansion and stabilization associated with long-term potentiation. J Neurosci 28:5740-51|
|Yang, Yunlei; Wang, Xiao-Bin; Frerking, Matthew et al. (2008) Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation. Proc Natl Acad Sci U S A 105:11388-93|
|Deng, Vivianne; Matagne, Valerie; Banine, Fatima et al. (2007) FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet 16:640-50|
|Partovi, Dara; Frerking, Matthew (2006) Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors. Neuropharmacology 51:1030-7|
|Frerking, M; Ohliger-Frerking, P (2006) Functional consequences of presynaptic inhibition during behaviorally relevant activity. J Neurophysiol 96:2139-43|
|Frerking, M; Schulte, J; Wiebe, S P et al. (2005) Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission. J Neurophysiol 94:1528-40|
|Frerking, Matthew (2004) When astrocytes signal, kainate receptors respond. Proc Natl Acad Sci U S A 101:2649-50|
|Ohliger-Frerking, Patricia; Wiebe, Sherman P; Staubli, Ursula et al. (2003) GABA(B) receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains. J Neurosci 23:4809-14|
|Frerking, Matthew; Ohliger-Frerking, Patricia (2002) AMPA receptors and kainate receptors encode different features of afferent activity. J Neurosci 22:7434-43|