Electrophysiological and pharmacological characterization of GABAA receptor-mediated currents

GABA_A receptors constitute important inhibitory neurotransmitter receptors in the central nervous system and have a staggering variety of receptor subtypes and thus binding sites. Not only GABA_A receptor targeting drugs such as benzodiazepines or sedative general anaesthetics elicit effects at these receptors by allosteric interaction sites, but a wide range of small molecules have been identified as GABA_A receptor modulators, including multiple antipsychotic and antidepressant medications not intentionally targeting these receptors.

Hippocampal dysfunction has long been considered to contribute to the pathophysiology of schizophrenia and post-mortem studies in the brains of patients with schizophrenia suggest that hippocampal expression of GABA_A receptors is altered in a subtype-selective manner. The α5 GABA_A receptor subunit, which is characterized by its relatively limited distribution and high abundance in the hippocampus, has been in the focus of clinical and preclinical schizophrenia research. The search for α5-containing subtype-preferring ligands has provided many compounds widely used in research. These molecules exert allosteric modulatory effects that can be GABA-induced current enhancement or reduction.

Negative modulation of α5-containing GABA_A receptors has been shown to promote hippocampal gamma oscillations, long-term potentiation, and learning, as well as have antidepressant effects associated with restored synaptic strength in the form of increased glutamatergic excitatory activity. In the 80s and 90s, the interactions of several antipsychotics with GABA_A receptors have been considered serious candidates for eliciting part of the therapeutic effects (see studies from Squires & Saederup). Another key protein in neural plasticity, learning and memory is the calcium/calmodulin-dependent protein kinase II (CaMKII). γ-Hydroxybutyric acid (GHB) is a natural brain metabolite of GABA and CaMKIIa was recently found to be the GHB high-affinity target. GABA_A receptors have also been studied as possible targets for GHB and analogue ligands. The role of GABA_A receptors in mediating effects of GHB has been controversial.