D'Epifanio, B. | Search bioRxiv

bioRxiv2025

Developmental excitation-inhibition imbalance permanently reprograms autism-relevant social brain circuits

An influential theory proposes that an imbalance between excitation and inhibition (E:I) plays a central role in the etiology of autism and related developmental disorders. However, controversy exists as to whether this imbalance is a direct causal mechanism for autism, or a compensatory response to other primary etiological factors. Using chemogenetic manipulations in neonatal mice, we show that a transient E:I imbalance during development is sufficient to permanently reprogram autism-relevant social brain circuits. Chemogenetically manipulated mice exhibit lifelong impairments in sociability, persistent dysregulation of multiple autism-risk synaptic genes, and sustained cortical hyperexcitability in adulthood. Importantly, these social impairments are robustly rescued by pharmacological inhibition of neuronal excitability. Developmental E:I imbalance also disrupts functional connectivity in social brain regions enriched for transcriptionally dysregulated genes, suggesting a convergence of transcriptional and circuit-level pathology. Finally, multivariate modelling shows that behavioral dysfunction in chemogenetically manipulated animals closely associates with disrupted connectivity between prefrontal and mesolimbic dopaminergic regions. Collectively, our findings reconcile conflicting theories in the field and point to activity-dependent transcriptional remodeling as a foundational mechanism by which transient E:I imbalance during development can cause lasting, autism-relevant circuit dysfunction.

neuroscience↗

bioRxiv2024

Connectomic and behavioral alterations in creatine transporter deficiency are partially normalized by gene therapy

Creatine Transporter Deficiency (CTD) is an X-linked disorder due to the loss of SLC6A8 gene and presenting with low brain creatine, intellectual disability, autistic-like behavior and seizures. No treatments are available yet for CTD, and little is known about the brain circuit alterations underlying its pathological endophenotypes. Here, we tracked brain network and behavioral dysfunction in a murine model of CTD at two stages of disease progression. fMRI mapping revealed widespread disruption of brain connectivity in Slc6a8-KO mice, with robust somatomotor hypoconnectivity in juvenile animals, and weaker and more focal alterations of cortical and subcortical connectivity in adulthood. Notably, perinatal AAV-mediated expression of human SLC6A8 in Slc6a8- KO mice robustly prevented juvenile fMRI hypoconnectivity, an effect accompanied by the regression of multiple translationally relevant phenotypes, including reduced stereotyped movements, improved declarative memory and increased body weight, all of which persisted into adulthood. However, early cognitive deficits, impairments in working memory and residual fMRI hypoconnectivity in adult mice were not ameliorated by gene therapy. Furthermore, significant cognitive impairments were observed in WT mice receiving gene therapy, highlighting a potential detrimental effect of ectopic expression of SLC6A8 in healthy brain circuits. Finally, multivariate modeling in adult mice revealed a basal forebrain network whose activity was associated with behavioral performance and modulated by brain creatine levels. This brain-behavior relationship was disrupted in Slc6a8-KO mice. Our results document robust network disruption in CTD and demonstrate that CTD pathology can be partially alleviated by perinatal genetic expression of SLC6A8, providing a foundation for the future development of experimental therapies for this genetic disorder.

neuroscience↗