Biology subjects

Balestrini, S.

Publications and source records attributed to Balestrini, S..

2 recordsLinked to original sources

bioRxiv2026

Non-syndromic autism-associated SCN2A variants selectively exert dominant-negative effects on NaV1.2 channels.

The voltage-gated Na+ channel Nav1.2 has a key role for the initiation and propagation of action potentials and therefore in neuronal excitability in brain development and function. Genetic variants of the encoding gene SCN2A cause various neurodevelopmental phenotypes with infantile-childhood onset. Here, we investigated the functional impact on hNav1.2 function of 15 variants associated with pure non-syndromic ASD (nsASD), ASD with epileptic activity, developmental and epileptic encephalopathy or schizophrenia. Only nsASD variants caused a complete loss of function hNav1.2 channels when expressed alone in tsA-201 cells and cultured neocortical neurons. Co-expression of the WT and mutant channels mimicking heterozygosis revealed that ASD mutants induce a dominant negative effect. Using different strategies to impair the domains of the channels that have been suggested to be implicated in the interaction of two Nav subunits, we reversed the dominant negative effect of ASD mutants on WT channels. These findings identify in heterologous systems a mechanistically distinct class of SCN2A variants implicated in nsASD, defined by dominant-negative loss of Nav1.2 function, with potential utility as a biomarker for genetic counseling, patient stratification, and the development of precision therapeutic strategies.

neuroscience↗

bioRxiv2026

Impaired Associative Memory, Inference, and Theta Dynamics in Postictal Psychosis of Epilepsy

Postictal psychosis (PIP) is a severe complication occurring in 2% of people with epilepsy (PWE) whose underlying pathophysiology remains poorly understood. Although historically considered separate from other forms of psychosis, newer evidence demonstrates a shared genetic susceptibility. People with schizophrenia are typically impaired at both associative learning and inferring connections between overlapping associations. Successful associative encoding, retrieval, and inference can each be predicted by changes in frontotemporal theta band activity, which is impaired in rodent models and people with schizophrenia. Here, we recorded high-density scalp EEG from PWE with history of PIP and well-matched control participants while they undertook a memory inference task. We found that associative memory and inference were both impaired in the PIP group, despite no difference in item recognition. Moreover, we found disrupted theta activity during memory encoding and the retrieval of inferred associations in PWE with PIP that likely originated from the medial temporal and frontal lobes. These results suggest a pattern of behavioural deficits and altered neural dynamics common to both PIP and schizophrenia. Interpreted in conjunction with previous genetic studies, they may reflect shared neural mechanisms contributing to psychopathology in both conditions and argue that PIP is a model of more general psychoses.

neuroscience↗