CORTICAL PATTERNING ABNORMALITIES IN A CHARGE SYNDROME MOUSE MODEL

Heterozygous, loss-of-function mutations in the CHD7 (Chromodomain Helicase DNA-binding factor 7) gene cause CHARGE syndrome, a neurodevelopmental disorder associated with executive dysfunction and mild learning difficulties. Previous work from our group has suggested that Chd7 haploinsufficiency in the mouse differentially affects anterior and posterior regions of the neocortex. To test if CHD7 has a role in anterior-posterior patterning of the developing neocortex, we quantified expression of key patterning genes in the anterior-, mid- and posterior embryonic neocortex in a B6;129S-Chd7^{GT(S20-7E1)SOR/DMMJ} heterozygous (Chd7^gt/+) mouse model. Expression of Nr2f1 (COUP-TF1) was transiently reduced in the posterior neocortex at e12.5 in comparison to wildtype controls. Sp8 expression was increased in the posterior e12.5 Chd7^gt/+ neocortex and decreased in the anterior neocortex at e16.5. These findings suggest a marked disruption of the expression gradients of key transcriptional regulators along the anterior-posterior axis of Chd7^gt/+ neocortices. Early postnatal phenotyping of Chd7^gt/+ mice revealed reduced growth, and deficits in socio-communicative behaviour and righting reflex when compared to wildtype controls, recapitulating the developmental delay and growth deficit observed in CHARGE syndrome. Adult Chd7^gt/+ mice displayed learning and memory deficits in the object location memory, novel object recognition, and contextual fear conditioning tests. Furthermore, mice exhibited improved performance on the accelerating rotarod, which may reflect an enhancement of corticostriatal drive observed in other neurodevelopmental mouse models. Together these data suggest that abnormalities in the anterior-posterior patterning of the neocortex may underlie altered neocortical circuitry and behavioural changes in a neurodevelopmental disorder.