CHARACTERISATION OF MURINE LAYER-6B DURING PERINATAL CORTICAL DEVELOPMENT AND ITS ROLE IN AUTISM ASSOCIATED BEHAVIOURS

Autism Spectrum disorder (ASD) is a myriad of neurodevelopmental disorders, affecting 1 in 100 individuals worldwide. Thalamocortical circuit dysfunction is emerging as a key contributor to the symptoms of ASD, including social impairments. These circuits form during mid-fetal development, a critical period marked by the presence of the cortical subplate, a transient but essential structure guiding thalamocortical connectivity. During early postnatal development in the murine brain, a large percentage of subplate neurons undergo apoptosis and only a subset of neurons persists into adulthood as layer 6b (L6b). Aberrant development of subplate, leads to cortical hyperexcitability, and autism-like behaviours in mice. Further, post-mortem studies autistic individuals reveal increased numbers and disorganization of white matter interstitial neurons, the human equivalent of L6b cells. In mice, L6b neurons exhibit increased dendritic arborization and spine density, on the modulation of PTEN. PTEN is a high-confidence ASD associated risk gene, which regulates neuronal survival and morphology by modulation of growth factor/ PI3K signalling. Here, we investigated a mouse line with conditional deletion of PTEN in L6b specific Drd1 neurons. In summary, the anatomical, morphological and electrophysiological characterisation of L6b in these mice, using confocal microscopy and Whole-cell patch clamp techniques respectively, indicate a PTEN dependent developmental modulation within this L6b specific neuronal subpopulation. Further, the behavioural characterisation of the conditional PTEN deficient adult mice indicate ASD associated deficits, solidifying the model. Together, our findings support a developmental trajectory suggesting that the disrupted development in L6b contributes to lasting thalamocortical circuit dysfunction and ASD-related behavioural deficits.