Physiology and Pharmacology of GABAA receptors: The Brakes in the Brain

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Inhibitory neurotransmission in the brain is mostly mediated by gamma-aminobutyric acid type A (GABAA) receptors. These receptors are involved in both phasic inhibition (point-to-point inhibition, synaptic transmission) and tonic inhibition (diffuse form of inhibition, brain homeostasis). In this thesis the functional and pharmacological properties of GABAA receptors expressed in brain slices or in Sf 9 cells were studied.

GABAA receptors expressed extrasynaptically are believed to be involved in tonic inhibition. In hippocampal dentate gyrus granule cells we identified and characterized three types of extrasynaptic receptor types (GABARex) that varied in their affinity for GABA, maximal single-channel conductance and sensitivity to drugs. For the first time we showed how the GABA concentration determines the conductance of GABAA receptors in brain tissue. There is thus a direct link between the extracellular GABA concentration and the level of the tonic inhibition, providing dynamic control.

It is only within the last ten years or so that the tonic inhibition was discovered and only recently has it gained widespread interest. One reason is that it has become quite clear that the first site of action and probably often the most important site of action of drugs are the extrasynaptic receptors. We found that a drug now in clinical trials (THIP) at the clinically relevant concentration activates these extrasynaptic receptors.

It has been assumed that spontaneous openings of the receptors are only functionally significant in receptor complexes containing the epsilon-subunit or mutations. We show that alpha/beta and alpha/beta/gamma?receptors can open spontaneously and be modified by drugs. The capacity to open spontaneously may be vital for fast responses such as at synapses. This suggests that the functional properties of receptors located at synapses and outside of synapses (extrasynaptic receptors: GABARex) differ. Those at synapses open rapidly (ms) whereas those at extrasynaptic sites open after a delay of ten to hundreds of seconds. This functional difference is very important in terms of brain function as it ensures fast flow of information (synaptic transmission) but in a controlled way that is set by the gain and the time window for synaptic transmission integration via the tonic inhibition.

By using the compound SR95531, we constructed a model that accounts for activation and inhibition of both phasic- and tonic-like currents in an expression system. This model can be used to calculate what concentrations of the inhibitor to use to specifically block certain GABARex receptors in brain tissue to study how a particular population of GABARex contributes to the tonic inhibition and how it affects both excitatory and inhibitory synaptic transmission.

Details

Authors
  • Catarina Lindquist
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Physiology
  • Pharmaceutical Sciences

Keywords

  • Physiology, Fysiologi, Ion channels, GABA, Inhibition
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • Bryndis Birnir, Supervisor
Award date2005 Oct 8
Publisher
  • Molecular and Cellular Physiology, Lund University
Print ISBNs91-85439-67-3
Publication statusPublished - 2005
Publication categoryResearch

Bibliographic note

Defence details Date: 2005-10-08 Time: 10:00 Place: Segerfalk lecture hall, BMC, Sölvegatan 17, Lund External reviewer(s) Name: Korpi, Esa Title: Professor Affiliation: University of Helsinki, Finland --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: GABA Channels in Physiology and Pharmacology (013241570)