Spellman, T. | bioRxiv Science

bioRxiv2025

Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice

In autism spectrum disorder (ASD), a neurodevelopmental disorder with social-cognitive deficits, macrocephaly occurs in 20% of patients with severe symptoms. However, the role of macrocephaly in ASD pathogenesis remains unclear. Here, we address the mechanistic link between macrocephaly and ASD by investigating a novel ASD-associated gain-of-function A1877T mutation in ASPM (abnormal spindle-like microcephaly-associated). ASPM is a key regulator of cortical size and cell proliferation expressed in both excitatory and inhibitory neuronal progenitors but not in differentiated neurons. We found that Aspm gain-of-function knock-in mice exhibit macrocephaly, excessive embryonic neurogenesis with expanded outer radial glia, an increased excitatory-inhibitory (E-I) ratio, brain hyperconnectivity, and social-cognitive deficits with male specificity. Our results suggest that macrocephaly in ASD is not a proportional expansion of excitatory and inhibitory neurons, but a shift in the E-I ratio, independent of the expression patterns of the causative gene. Thus, macrocephaly alone can cause a subset of ASD-like symptoms.

neuroscience↗

bioRxiv2019

Prefrontal deep projection neurons enable cognitive flexibility via persistent feedback monitoring

Cognitive flexibility, the ability to alter ones strategy according to changing stimulus-response-reward relationships, is critical for acquiring and updating learned behavior. Attentional set-shifting, a test of cognitive flexibility, depends on the activity of prefrontal cortex (PFC). It remains unclear, however, what specific role PFC neurons play and how they interact to support set-shifting. One widely held view is that prefrontal activity biases sensorimotor responses by mediating attention. Using optogenetics and 2-photon calcium imaging, we demonstrate that, while PFC activity does encode attentional sets, this activity does not bias sensorimotor responses. Rather, PFC activity enables set-shifting by encoding trial feedback information, a role it has been known to play in other contexts. We identify a circuit-level mechanism that supports feedback monitoring through persistent, recurring activity bridging multiple trials. Unexpectedly, the functional properties of PFC cells did not vary with their efferent projection targets in this context. Instead, representations of trial feedback formed a topological gradient, with cells more strongly selective for feedback information located further from the pial surface and receiving denser afferent inputs from the anterior cingulate cortex. Together, these findings identify a critical role for deep PFC projection neurons in enabling set-shifting through behavioral feedback monitoring.

neuroscience↗