Abnormal whisker-dependent behaviors and altered cortico-hippocampal connectivity in Shank3b−/− mice

Abstract

Abnormal tactile response is 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. The neural underpinnings of these 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. 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. Sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA induction, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutants, in the absence of altered connectivity between S1 and other somatosensory areas. Impaired crosstalk between hippocampus and S1 might underlie Shank3b−/− hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable somatosensory dysfunction in ASD.

Gene expression profiling in trigeminal ganglia from Cntnap2-/-and Shank3b-/-mouse models of autism spectrum disorder

“…It should be noted that a similar upregulation in mRNA expression has been shown in the cerebellum and parietal cortex of individuals with ASD (Fatemi et al, 2014). Upregulation found in GABAergic markers in the trigeminal ganglia can be consequently interpreted as underlining increased inhibition and thus giving way to hyporeactive/hyposensitive behaviors in adult Shank3b -/- and Cntnap2 -/- mice (Balasco et al, 2020; Balasco et al, 2021). In juvenile mice, on the other hand, an upregulation was found among Shank3b -/- TG for Gabrd, a gene whose dysfunction promotes psychomotor delay and epilepsy (Windpassinger et al, 2002).…”

“…Mouse lines harboring ASD-relevant mutations have been recently used to assess the neurobiological underpinnings of abnormal sensory responses in ASD within the central and the peripheral nervous system (He et al, 2017;Balasco et al, 2019Balasco et al, , 2020Chelini et al, 2019;Orefice, 2020;Pizzo et al, 2020). Given the relevance of the whisker system in mice, the assessment of TG neurons (which mediate tactile sensitivity from the whiskers) represents a promising tool to study somatosensory processing defects in ASD.…”

“…This protein belongs to the family of Shank proteins and therefore acts as a major scaffolding protein within the postsynaptic density of excitatory neurons (Jiang & Ehlers, 2013). As a syndrome, PMS is described by intellectual disability, speech and developmental delay, and importantly ASD-related behaviors such as problems in communication and social interaction (Phelan & McDermid, 2010), as well as sensory hypo reactivity to tactile stimulation (Balasco et al, 2020). CDFE is caused by a recessive nonsense mutation in the CNTNAP2 gene which codes for CASPR2.…”

“…Given the fundamental role of early-life tactile experiences in shaping the acquisition of normal social behavior and communication skills in humans as well as in rodents, we hypothesized that peripheral tactile processing defects might contribute to ASD symptomatology. We recently reported aberrant somatosensory processing in the central nervous system of adult Shank3b and Cntnap2 mutant mice following whisker stimulation (Balasco et al, 2020; Balasco et al, 2021). Nonetheless, to infer a possible peripheral contribution to such defects, here we performed a gene expression profiling of TG in Cntnap2 -/- and Shank3b -/- mice, in both adult and juvenile stages.…”

Automated decoding the mouse body postures in a whisker nuisance test

“…Mouse response to the whisker stimulation is then quantified using predetermined behavioral categories (BCs). BCs used thus far aim to deconstruct the animals' response by exploring independent instances of either anxious or explorative behaviors [1][2][3][4] . Previous studies have shown how behavioral abnormalities identified with the WNt are reliably well-matched with similar observation in people with ASD [5][6][7][8] , showing a solid translational validity and opening the possibility of directly investigating the neurobiological underpinning of this common phenotypic trait [1][2][3] .…”