Impairments in sensory-motor gating and information processing in a mouse model of haploinsufficiency.

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders. Haploinsufficiency of , encoding a histone methyltransferase, is associated with several neurodevelopmental disorders, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of haploinsufficiency ( ), we examined a number of brain and behavioural endophenotypes of relevance to neurodevelopmental disorders. Specifically, we show that mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory, and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity. The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of mRNA expression in hippocampus, suggests that haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with haploinsufficiency.