Herlt, T; (2016) Properties of GABAergic inhibition of the medial prefrontal cortex. Doctoral thesis , UCL (University College London).

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Abstract

Gamma-aminobutyric acid type A receptors (GABAARs) are the main inhibitory neurotransmitter receptors in the central nervous system. As such, they play a pivotal role in synchronising neuronal network activity in the brain and their dysregulation has been implicated in numerous neuropsychiatric diseases such as depression, anxiety and schizophrenia. GABAARs are ligand-gated heteropentamers and can be modulated either directly or indirectly by a number of therapeutically-relevant compounds, such as the benzodiazepines, or by endogenous neuromodulators, such as the neurotransmitters dopamine and serotonin, and by neurosteroids. While much is known about the function of GABAARs, their modulation and interaction with neuromodulators and other neurotransmitter systems are less well understood. In particular, their role in the prefrontal cortex (PFC), a brain area strongly involved in motivation and planning, which is often negatively affected in neuropsychiatric disease, remains to be elucidated. The aims of this research project were to characterise synaptic and tonic inhibition in the PFC, explore dopaminergic and neurosteroid modulation of GABA inhibition and to examine effects on neuronal excitability. We focused on α2 subunit-containing GABAARs because of their role in anxiety and preferred subcellular localisation at the axon initial segment (AIS), an area that is critical for regulating neuronal spike output. Contrary to previous findings, we could not detect an effect of dopamine D4 receptor activation on GABA inhibition. However, using a mouse model expressing neurosteroid-insensitive GABAAR α2 subunits, we found evidence for a significant differential involvement of this subunit and neurosteroid modulation in GABAergic synaptic inhibition between various layers of the PFC. We discovered that alterations in phasic GABA-mediated inhibition had no significant effects on pyramidal cell excitability, whilst increasing tonic inhibition reduced cell firing. Overall, this study demonstrates that tonic GABA inhibition has a more important role to play in regulating cortical network function than previously thought.

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