Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

Abstract

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B −/− mouse model of ASD. Male and female Shank3B −/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.

Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior

“…In particular, we found an increase in the recruitment of prefrontal neurons during social interaction. This mirrors a recent study which found hyperdynamic response to whisker stimulation in the same mice (Chen et al , 2020), possibly reflecting GABAergic circuit dysfunction and/or homeostatic compensations (Nelson and Valakh, 2015). (Note: these findings cannot be ascribed simply to the fact that Shank3 KO mice spend less time engaged in social interaction than their wild-type littermates; reduced interaction time would tend to reduce statistical power and thereby reduce the number of neurons that change their activity more than expected by chance.…”

“…We were curious whether there might be conditions under which these phenomena – the occurrence of multineuron combinations of coactivity during social behavior, and the ability of correlations to enhance the transmission of information about social behavior – might be impaired. To explore this, we performed microendoscopic GCaMP imaging in mice lacking the autism-associated gene Shank3 (Peça et al , 2011; Duffney et al , 2015; Chen et al , 2020). These mice have been extensively studied as models of Phelan-McDermid syndrome, which often includes autism as a clinical feature.…”

Shifted Phase of EEG Cross-Frequency Coupling in Individuals with Phelan-McDermid Syndrome

“…Developmental effects are particularly important to consider in PMS given the known molecular and electrophysiological functions of SHANK3, including effects on plasticity. SHANK3 provides scaffolding in the postsynaptic density of glutamatergic synapses (6), and Shank3 mutant mouse models have therefore demonstrated decreased excitability of glutamatergic (8,9,14,15) and GABAergic neurons (11). Plasticity is also impaired in Shank3 mutants (13).…”

“…Power was computed across frequencies using a three taper multitaper window (49). Power was then computed for a number of frequency bands: Delta [1-4 Hz), Theta [4-8 Hz), Alpha [8][9][10][11][12], Beta [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and Gamma . Total power was computed as all frequencies between .…”

Lateralized decrease of parvalbumin+ cells in the somatosensory cortex of ASD models is correlated with unilateral tactile hypersensitivity

“…Behavioral hypersensitivity of the dominant paw reported in the present study in Shank3 -/and Cntnap2 -/mice could simply be due to the observed lateralized decrease in PV + neurons in the dominant somatosensory cortex. A recent in vivo population calcium imaging in the somatosensory cortex has shown increases in both spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons resulting in sensory hyper-reactivity in Shank3 -/mice (Chen Q et al 2020). However, this study did not compare the dominant and nondominant paw sensitivity or sensory-evoked firing properties of the two hemispheres.…”