Summary
Objective:
GABAA receptor subunit gene mutations are significant causes of epilepsy, which are often accompanied with various neuropsychiatric comorbidities, but the underlying mechanisms are unclear. It has been suggested that the comorbidities are caused by seizures as they often present in severe epilepsies. However, findings from both humans and animal models argue against this conclusion. Mutations in the GABAA receptor γ2 subunit gene GABRG2 have been associated with anxiety alone or with severe epilepsy syndromes and comorbid anxiety, suggesting a core molecular defect gives rise to the phenotypical spectrum. Here we determined the pathophysiology of comorbid anxiety in epilepsy and identified the central nucleus of the amygdala (CeA) as a primary neurosubstrate and a potential rescue via neuromodulation of CeA neurons.
Methods:
We used brain slice recordings, subcellular fractionation and western blot, immunohistochemistry, confocal microscopy and a battery of behavior tests in combination with a chemogenetic approach to characterize anxiety and its underlying mechanisms in a Gabrg2+/Q390X knockin mouse and a Gabrg2+/− knockout mouse, each associated with a different epilepsy syndrome.
Results:
We found that impaired GABAergic neurotransmission in CeA underlies anxiety in epilepsy, which is due to reduced GABAA receptor subunit expression resulting from the mutations. Impaired GABAA receptor expression reduced GABAergic neurotransmission in CeA, but not in BLA. Activation or inactivation of inhibitory neurons using a chemogenetic approach in CeA alone modulated anxiety-like behaviors. Similarly, pharmacological enhancement of GABAergic signaling via γ2 subunit-containing receptors rescued the anxiety.
Significance:
Together, these data demonstrate the molecular basis for a comorbidity of epilepsy and suggest that impaired GABAA receptor function in CeA due to mutation per se could at least contribute to anxiety. Modulation of CeA neurons could cause or suppress anxiety, suggesting a potential use of CeA neurons as therapeutic targets for treatment of anxiety in addition to traditional pharmacological approaches.