The Role of Extrasynaptic GABAA Receptors in Regulation of Inhibitory Synapses

Open Access
Author:
Zhang, Ce
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Bernhard Luscher, Honors Advisor
  • Dr Gong Chen, Thesis Supervisor
Keywords:
  • GABA
  • neuroscience
  • biology
  • brain inhibition
Abstract:
Inhibition in the brain is largely controlled by type-A GABA (γ-aminobutyric acid) receptors (GABAARs). Deficits in the functional expression of GABAARs are implicated in epilepsy, anxiety disorders, schizophrenia, cognitive deficits, depression, and substance abuse, and GABAARs are also targets for the therapeutic effects of many clinically important drugs. Inhibition can be mediated by synaptic GABAARs, which are activated in a transient or phasic manner. Moreover, extrasynaptic GABAARs play an important role in mediating tonic inhibition in the brain. Neural mechanisms that contribute to the balance between synaptic and extrasynaptic GABAAR activation are still largely unknown. Here we show that overexpression of the extrasynaptically localized α6β3δ, α6, and α5 subunits in cortical neurons can regulate the number of GABAergic synapses, indicated by glutamic acid decarboxylase (GAD)-positive puncta found on dendrites. GAD is an enzyme that catalyzes the decarboxylation of glutamate to GABA, and serves as a proxy marker for inhibitory synapses. We found that overexpression of α6β3δ, α6, or α5 alone caused a significant decrease in the number of GAD puncta compared to GFP-transfected control neurons. Thus, extrasynaptically localized α6β3δ, α6, or α5-containing receptors could also play a role in the regulation of inhibitory synapses. Based on our findings, we propose a novel hypothesis that synaptic and extrasynaptic GABAARs interact together to determine GABAergic synapse formation and function