Pilot studies for pharmacological investigations.

<div><p>Loss of function (LoF) mutations affecting the histone methyl transferase <i>SETD1A</i> are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of <i>Setd1a</i> haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male <i>Setd1a</i><sup>+/-</sup> mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male <i>Setd1a</i><sup>+/-</sup> mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in <i>Setd1a</i><sup>+/</sup> samples. In adulthood, we found enhanced acoustic startle responding in male <i>Setd1a</i><sup>+/-</sup> mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female <i>Setd1a</i><sup>+/-</sup> mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, <i>Setd1a</i> haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of <i>Setd1a</i> haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.</p></div>