Intellectual disability (ID) is a common neurodevelopmental disorder that can arise from genetic mutations ranging from trisomy to single nucleotide polymorphism. Mutations in a growing number of single genes have been identified as causative in ID, including ARHGEF9. Evaluation of 41 ARHGEF9 patient reports shows ubiquitous inclusion of ID, along with other frequently reported symptoms of epilepsy, abnormal baseline EEG activity, behavioral symptoms, and sleep disturbances. ARHGEF9 codes for the Cdc42 Guanine Nucleotide Exchange Factor 9 collybistin (Cb), a known regulator of inhibitory synapse function via direct interaction with the adhesion molecule neuroligin-2 and the alpha2 subunit of GABA(A) receptors. We mutate the Cb binding motif within the large intracellular loop of alpha2 replacing it with the binding motif for gephyrin from the alpha1 subunit (Gabra2-1). The Gabra2-1 mutation causes a strong downregulation of Cb expression, particularly at cholecystokinin basket cell inhibitory synapses. Gabra2-1 mice have deficits in working and recognition memory, as well as hyperactivity, anxiety, and reduced social preference, recapitulating the frequently reported features of ARHGEF9 patients. Gabra2-1 mice also have spontaneous seizures during postnatal development which can lead to mortality, and baseline abnormalities in low-frequency wavelengths of the EEG. EEG abnormalities are vigilance state-specific and manifest as sleep disturbance including increased time in wake and a loss of free-running rhythmicity in the absence of light as zeitgeber. Gabra2-1 mice phenocopy multiple features of human ARHGEF9 mutation, and reveal alpha2 subunit-containing GABA(A) receptors as a druggable target for treatment of this complex ID syndrome.
        
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Hines DJ, Contreras A, Garcia B, Barker JS, Boren AJ, Moufawad El Achkar C, Moss SJ, Hines RM (2022) Human ARHGEF9 intellectual disability syndrome is phenocopied by a mutation that disrupts collybistin binding to the GABA(A) receptor alpha2 subunit Mol Psychiatry
Hines DJ, Contreras A, Garcia B, Barker JS, Boren AJ, Moufawad El Achkar C, Moss SJ, Hines RM (2022) Mol Psychiatry