Reduced susceptibility to induced seizures in the Neuroligin-3R451C mouse model of autism

Abstract

Epilepsy is a common comorbidity in patients with autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, Neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3R451C (NL3R451C) and wild type (WT) mice. It has previously been reported that NL3R451C mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3R451C compared to WT mice following administration of both 20mg/kg PTZ (1.17±0.31 compared to 16.0±11.16 events/30min, NL3R451C versus WT, respectively) and 30mg/kg PTZ (7.5±6.54 compared with 27.8±19.9 events/30min, NL3R451C versus WT, respectively). NL3R451C mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first >3s duration clonic seizure; 14.5min versus 7.25min, 95% CI: 1.625–2.375, p=0.0009, NL3R451C versus WT, respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD.