Pangrazzi, L. | bioRxiv Science

bioRxiv2023

The interplay between oxidative stress and inflammation supports autistic-related behaviors in mice

Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that inflammation may contribute to ASD. Here we used RT-qPCR, RNA sequencing, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2 (Cntnap2-/-), a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress and inflammation as well as motor and social impairments in Cntnap2-/- mice. This was accompanied by improved function of microglia cells in NAC-treated mutant animals. Intriguingly, social deficits, cerebellar inflammation and microglia dysfunction were induced by NAC in Cntnap2+/+animals. Our findings therefore suggest that the interplay between oxidative stress and inflammation may support ASD-related behaviors in mice.

immunology↗

bioRxiv2021

Somatosensory processing deficits and altered cortico-hippocampal connectivity in Shank3b-/- mice

Abnormal tactile response is considered an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to tactile stimuli is often associated with the severity of ASDs core symptoms. Patients with Phelan-McDermid syndrome (PMS), caused by mutations in the SHANK3 gene, show ASD-like symptoms associated with aberrant tactile responses. However, the neural underpinnings of these somatosensory abnormalities are still poorly understood. Here we investigated, in Shank3b-/- adult mice, the neural substrates of whisker-guided behaviors, a key component of rodents interaction with the surrounding environment. To this aim, we assessed whisker-dependent behaviors in Shank3b-/- adult mice and age-matched controls, using the textured novel object recognition (tNORT) and whisker nuisance (WN) test. Shank3b-/- mice showed deficits in whisker-dependent texture discrimination in tNORT and behavioral hypo-responsiveness to repetitive whisker stimulation in WN. Notably, sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA in situ hybridization, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutant mice. Together, these findings suggest that impaired crosstalk between hippocampus and S1 might underlie Shank3b-/- hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable form of dysfunctional somatosensory processing in ASD. Significance StatementPatients with Phelan-McDermid syndrome, a syndromic form of ASD caused by mutation of the SHANK3 gene, often show aberrant responses to touch. However, the neural basis of atypical sensory responses in ASD remains undetermined. Here we used Shank3 deficient mice to investigate the neural substrates of behavioral responses to repetitive stimulation of the whiskers, a highly developed sensory organ in mice. We found that mice lacking the Shank3 gene are hypo-responsive to repetitive whisker stimulation. This trait was associated with reduced engagement and connectivity between the primary somatosensory cortex and hippocampus. These results suggest that dysfunctional cortico-hippocampal coupling may underlie somatosensory processing deficits in SHANK3 mutation carriers and related syndromic forms of ASD.

neuroscience↗