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Glycinergic and GABAergic inhibition in ventrobasal nuclei of rat thalamus

University of British Columbia

This thesis examines the major inhibitory systems in ventrobasal nuclei of rat thalamus. The ventrobasal nuclei participate in relay and processing of somatosensory information and generation of thalamocortical rhythms. Inhibitory synaptic responses play an essential role in function of ventrobasal thalamus. A major objective of this thesis is to examine the hypothesis that glycine receptors mediate inhibition in ventrobasal thalamus. The thesis pharmacologically characterizes the synaptic and extrasynaptic inhibition and describes synaptic inhibition originating in nuclei surrounding ventrobasal thalamus. The thesis further characterizes the biophysical properties of glycine and γ-aminobutyric acid type A (GABAA) receptors in thalamus. We established that α₁, and α₂ glycine receptor subunits are expressed in the ventrobasal nuclei, using immunohistochemical staining. The functional nature of these subunits was confirmed by demonstrating the effects of glycine receptor agonists on thalamocortical neurons. Functional glycine receptors were likely limited to larger type-1 thalamocortical neurons. Synaptic inhibition evoked from medial lemniscus uncovered a heterogeneous inhibitory input to ventrobasal thalamus. GABAA and glycine receptors mediated synaptic inhibition in a majority of neurons. Inhibition in two minor groups of neurons was exclusively mediated by either GABAA or glycine receptors. Occasionally, there was an additional GABAB component of synaptic inhibition. The medial lemniscal mediated inhibition was likely polysynaptic, and resulted from co-transmission of GABA and glycine. Stimulations within surrounding nuclei evoked monosynaptic inhibition. The highest relative glycinergic strength was evoked from the ethmoid nucleus. Another major finding of these studies was the diverse kinetics of the glycinergic inhibition. The observations were consistent with the activation of two kinetically distinct populations of glycine receptors, segregated under separate nerve terminals. The kinetics of synaptic receptors mirrored the kinetics of extrasynaptic receptors. Synaptic channels displayed higher Cl⁻ permeability than their extrasynaptic counterparts. These studies involved examination of previous methods. The specificity of strychnine was investigated and the optimal concentration for discrimination between glycine and GABAA receptors was established. Synaptic currents were simulated to examine the sources of error in non-stationary fluctuation analysis. This procedure resulted in an improved method for non-stationary fluctuation analysis. In summary, this thesis unveils the heterogeneous nature of synaptic inhibition in somatosensory thalamus. The findings open frontiers in the research and development of new drugs targeting glycinergic inhibition in the thalamus.

Text

2010-01-16

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http://hdl.handle.net/2429/18507

Neuroscience

University of British Columbia

UBCV

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