DISRUPTED THALAMIC ENCODING OF TACTILE PROCESSING IN JUVENILE SHANK3B MUTANT MICE

Tactile experience is essential during neurodevelopment, influencing sensory, motor and cognitive functions through complex, finely tuned thalamocortical and corticothalamic circuits. Early tactile stimulation is particularly important for the development of social behavior and communication skills, which are impaired in autism spectrum disorders (ASD). Somatosensory processing involves several brain structures, notably the ventrobasal (VB) and posteromedial (POm) thalamic nuclei, inhibitory reticular thalamic nucleus (TRN), and primary somatosensory cortex (S1). Proper function of each component, as well as accurate connectivity and excitation/inhibition (E/I) balance within these circuits, is critical for the correct encoding of touch. However, little is known about how the neural circuits underlying sensory processing change in ASD during early life. This study explores tactile deficits and circuit alterations in Shank3B KO mice. Using hind-paw stimulation, we found a developmental shift from tactile hyposensitivity in juveniles, similar to patients, to hyper-reactivity in adult KO mice. In vivo recordings in awake animals revealed a paradoxical increase in the number of responsive neurons in the VB, despite a reduction in response amplitude. Ex vivo electrophysiology showed intrinsic hypoexcitability and a decreased E/I ratio in VB neurons. Optogenetic inhibition of VB neurons in WT mice reproduced tactile hyposensitivity, while attempts to rescue the phenotype through neuronal activation failed, suggesting E/I imbalance cannot be restored simply by increasing VB excitation. However, increasing VB inhibition via chemogenetic activation of TRN rescued the phenotype. These findings elucidate a mechanism underlying early-life tactile deficits and provide a basis for further exploration of sensory processing abnormalities in ASD.