Lateralized change in cortical neural networks in shank3 mutant mice

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Project summary Aberrant lateralization in brain structure and function is linked to the neurodevelopmental disorders such as autism spectrum disorders (ASD). We have recently reported a lateralized decrease in the number of parvalbumin expressing (PV+) basket cells (BCs) in L2/3 of the somatosensory cortex in the dominant hemisphere of adult Shank3-/- mouse model of ASD. The dominant hemisphere was identified by a reaching task to define each animal’s dominant forepaw. We further used a marker to recognize the specific extracellular matrix enwrapping BCs and found that the number of BCs was not different between the two hemispheres, but rather, some BCs did not express detectable levels of PV (PV- BCs). Remarkably, we showed a mechanical hypersensitivity in the dominant paw correlated with the decrease in the number of PV+ BCs in the corresponding cortex. However, almost nothing is known regarding the developmental trajectory of the observed lateralization in BCs and the impact of a reduction in PV expression on the properties of BCs or pyramidal neurons in local neural circuits. In the present proposal, we will first characterize interhemispheric differences in BC – pyramidal cell network properties in L2/3 of the somatosensory cortex in the Shank3-/- mouse by a combination of in vivo calcium (Ca2+) imaging during whisker stimulation and in vitro patch clamp recording. We investigate differences in the activity and electrophysiological properties of PV+ BCs and the atypical PV- BCs present in Shank3-/- mice. Next, we will evaluate changes in the output of the somatosensory cortex by in vivo Ca2+ imaging of L2/3 pyramidal cells in the barrel cortex during whisker stimulation in Shank3-/- mice. Furthermore, to determine the excitation / inhibition ratio directly, we will use patch clamp recording to study the synaptic inputs to L2/3 pyramidal cells during electrical stimulation of L4. Finally, we will identify the developmental trajectory of interhemispheric differences in the number of L2/3 PV+ and PV- BCs in the somatosensory cortex of the Shank3-/- mouse using immunohistochemistry. Results of the immunohistochemistry, electrophysiology and calcium imaging studies proposed here will significantly increase our knowledge about the role of lateralized changes in the dominant hemisphere in the pathophysiology of ASD and could provide the means for new therapeutic approaches.