POGZ MUTANT MOUSE MODEL OF AUTISM SPECTRUM DISORDER SHOWS ABNORMAL NEURAL ACTIVITY IN THE ANTERIOR CINGULATE CORTEX DURING SOCIAL BEHAVIOR

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication. Despite its high prevalence, neural pathogenesis of ASD is largely unknown. The anterior cingulate cortex (ACC) is critically involved in various cognitive processes and has been reported to be associated with social communication. Recent studies suggest that impaired ACC function may be associated with social impairment in ASD, however the detailed underlying neural mechanisms are unclear. We previously demonstrated that a mouse model carrying an ASD patient-derived mutation in POGZ, one of the genes most significantly associated with ASD (POGZ mutant mice), showed ASD-like behavioral deficits, including impaired social communication. Aims & Objectives Here, to understand the neural mechanisms behind the impaired social communication in POGZ mutant mice, we measured the neural activity in the ACC by fiber photometry in freely moving mice. Methods Fiber photometry was employed to examine neural activities in freely moving mice participating in social interaction tests. Wild-type (WT) and POGZ mutant mice were injected with AAV-CamKIIα-GCaMP6f in the ACC, followed by the implantation of optic cannula. Ca2+ signals were recorded during 5-minute social interaction tests, at a minimum of 3 weeks post-injection. Results We initially confirmed that POGZ mutant mice exhibited reduced social interaction time compared to their WT littermates, consistent with our previous report. Through fiber photometry recordings, we observed an elevation in Ca2+ signals of ACC pyramidal neurons upon the introduction of intruder mice in both WT and POGZ mutant mice. Remarkably, the average Ca2+ signals of ACC pyramidal neurons in the presence of intruder mice were significantly higher in POGZ mutant mice. In contrast, the neural activity in the ACC pyramidal neurons in POGZ mutant mice displayed reduced responsiveness to the initiation of each social investigation in comparison to that in WT mice. These results suggest that the ACC neural activity governing social behavior is impaired in POGZ mutant mice. Discussion & Conclusion These findings suggest a neurobiological link between the dysregulation of neural activity in ACC pyramidal neurons and social impairment in POGZ mutant mice, thereby shedding light on potential avenues for the development of novel therapeutics for ASD.