While hippocampal dysfunction has long been implicated in the spatial learning and memory deficits observed in Autism Spectrum Disorder (ASD), recent research published in Science Advances presents a compelling shift in focus towards the perirhinal cortex (PRC). Investigating three distinct genetic mouse models of ASD (Scn2a^+/-, Fmr1^-/-, and Cdkl5^-/-), the study revealed that abnormalities in the PRC, characterized by cortical hypoactivity, are a critical driver of these cognitive impairments. This finding challenges the singular emphasis on the hippocampus and suggests a more distributed neural circuit underlying learning deficits in ASD.

The study’s rigor was significantly enhanced by the utilization of specific Cre driver mouse lines obtained from the Mutant Mouse Resource and Research Center (MMRRC). Drd3-Cre mice, allowing for targeted gene manipulation in the hippocampus, demonstrated that reducing Scn2a specifically in this region was insufficient to replicate the observed spatial learning deficits. Further refinement using Rbp4-Cre and Ntsr1-Cre lines from the MMRRC helped pinpoint the involvement of upper cortical layers, ultimately highlighting the PRC as a key region mediating these cognitive impairments across multiple genetic etiologies of ASD.

These findings hold significant promise for future research and therapeutic development. The successful rescue of spatial learning deficits and restoration of LTP in both the PRC and hippocampus through chemogenetic activation of PRC excitatory neurons across all three mouse models underscores the PRC as a potential convergent therapeutic target. This opens the door for exploring non-invasive neuromodulatory techniques, such as targeted transcranial magnetic stimulation (TMS) or transcranial focused ultrasound, aimed at enhancing PRC activity and potentially alleviating cognitive challenges in individuals with ASD. This research represents a crucial step towards a more nuanced understanding of the neurobiological basis of learning impairments in ASD and the development of targeted interventions.

Source: Perirhinal cortex abnormalities impair hippocampal plasticity and learning in Scn2a, Fmr1, and Cdkl5 autism mouse models