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Modulation of ligand-gated receptors in the central nervous system

University of British Columbia

Basal level neuronal excitability in the mammalian brain is fundamental for physiological brain functions. It is primarily maintained by a fine balance between two types of synaptic transmission: the excitatory transmission mediated by glutamate-gated ion channels including α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-D-aspartic acid receptors (NMDARs), and the inhibitory transmission mediated by chloride channels including γ-Aminobutyric acid receptors (GABAARs) found in the brain and glycine receptors (GlyRs) orginating in the spinal cord and brainstem. Therefore, understanding mechanisms by which these ligand-gated ion channels (LIGCs) are regulated is critical for our understanding of both brain functions and dysfunctions, and is the major focus of this thesis. In particular, this research project investigates: 1) how rapid alteration of AMPAR trafficking results in changes in strength of synaptic transmission, with a particular emphasis on its contribution to amygdala long-term potentiation (LTP) and depression (LTD), the two most well-characterized forms of synaptic plasticity, and 2) how excitatory transmitter glutamate modulates functions of the inhibitory GABAA and Gly receptors. In chaper 2 and 3, we show in lateral amygdale (LA) slices that the induction of LTP requires NR2A-containing NMDAR activation, while the expression of LTP requires AMPARs insertion (sensitive to TeTx or GluR1-derived peptide). On the contrary, the induction of LTD involves activation of NR2B-containing NMDARs and the expression of LTD involves AMPARs endocytosis (sensitive to GluR2-3Y peptide). The inhibitory receptors GABAARs and GlyRs are respectively activated by binding with their respective transmitters, GABA and glycine. In chapter 4 and 5, we show novel and unexpected findings where glutamate potentiates currents mediated by either GABAARs or GlyRs in neurons and in HEK cells over-expressing recombinant GABAARs and GlyRs. This potentiation was not dependent on activation of any known ionotropic or metabotropic glutamate receptors. Thus, our results strongly suggest that glutamate can allosterically potentiate the function of GABAARs and GlyRs, thereby blurring the traditional distinction between excitatory and inhibitory transmitters. Such a rapid homeostatic regulatory mechanism may have a significant role in tuning functional balance between synaptic excitation and inhibition in the central nervous system (CNS).

Text

2011-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/27082

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/