Holden, T.E.; (2006) Modulation of excitatory synaptic transmission to hippocampal interneurons by metabotropic glutamate receptors. Doctoral thesis , University of London.

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Abstract

The hippocampus is a medial temporal lobe structure implicated both in consolidation of experience into long-term memory and generation of epileptiform discharges. Information processing in the hippocampus occurs through interactions between glutamatergic granule cells and pyramidal neurons, and a smaller number of GABAergic inhibitory interneurons. Excitatory connections onto interneurons are a relatively poorly characterised class of synapse, yet they have a central role in mediating the recruitment of inhibitory drive within the hippocampus. This thesis describes investigation of modulation of excitatory synaptic transmission to interneurons in area CA1 of the hippocampus by metabotropic glutamate receptors (mGluRs). mGluRs are G protein-coupled heptahelical transmembrane receptors, which exert powerful modulatory effects upon synaptic transmission and neuronal excitability. Use of patch clamp electrophysiology in acute brain slices allowed synaptic responses elicited by stimulation of afferent inputs to be recorded in single neurons within a functionally intact network. The selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was found to acutely depress glutamatergic transmission to stratum radiatum interneurons in the rat hippocampal CA1 subfield. Both mGluRI and mGluR5 subtypes contributed to this phenomenon. DHPG-evoked depression was consistently accompanied by an elevation in paired-pulse ratio, implying a presynaptic mechanism of expression. However, it was also attenuated by blocking G protein and Ca2+ signalling within the postsynaptic neuron, arguing for a postsynaptic site of induction. The DHPG-evoked depression was unaffected by antagonists of GABAB and CB1 endocannabinoid receptors but was occluded when presynaptic P/Q-type Ca2+ channels were blocked. A heterosynaptic depression was observed in a test pathway when a high-frequency tetanus was delivered to an independent conditioning pathway. This depression was reversible and abolished by group I mGluR antagonists. Group I mGluRs thus provide a mechanism for population activity in glutamatergic synapses to influence synaptic excitation of cortical interneurons.

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