Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

The immediate early gene c-fos has long been known as a molecular marker of neural activity. The neuron’s activity is transformed into intracellular calcium influx through NMDA receptors and L-type voltage sensitive calcium channels. For the transcription of c-fos, neural activity should be strong enough to activate mitogen-activated protein kinase (MAPK) signaling pathway which shows low calcium sensitivity. Upon translation, the auto-inhibition by Fos protein regulates basal Fos expression. The pattern of external stimuli and the valence of the stimulus to the animal change Fos signal, thus the signal reflects learning and memory aspects. Understanding the features of multiple components regulating Fos signaling is necessary for the optimal generation and interpretation of Fos signal.

We report here a novel action of GABAergic synapses in regulating tonic firing in the mammalian brain. By using gramicidin-perforated patch recording in rat brain slices, we show that cells of the medial habenula of the epithalamus generate tonic firing in basal conditions. The GABAergic input onto these cells at postnatal days 18-25 generates a combinatorial activation of fast excitation and slow inhibition. The fast excitation, mediated by gamma-aminobutyric acid type A receptors (GABA A Rs), is alone capable of triggering robust action potentials to increase cell firing. This excitatory influence of GABAergic input results from the Cl(-) homeostasis that maintains intracellular Cl(-) at high levels. The GABA A excitation is often followed by a slow inhibition mediated by GABA B Rs that suppresses tonic firing. Interestingly, in a subpopulation of the cells, the GABA B inhibition exhibits a remarkably low threshold for synaptic activation in that low-strength GABAergic input often activates selectively the GABA B slow inhibition, whereas the GABA A excitation requires further increases in stimulus strength. Our study demonstrates that the dual activation of GABAergic excitation and inhibition through GABA A Rs and GABA B Rs generates distinct temporal patterns of cell firing that alter the cellular output in an activity-dependent manner.

An infrequently studied and potentially promising physiological marker for posttraumatic stress disorder (PTSD) is pupil response. This study tested the hypothesis that arousal-related pupil responses to threat would be differentially expressed in trauma-exposed individuals with or without PTSD. Eye-tracking technology was used to evaluate pupil response to threatening and neutral images selected from the International Affective Picture System. Forty trauma-exposed individuals were recruited for participation between 2010–2014. Sixteen of them met diagnostic criteria for PTSD. Individuals with PTSD showed significantly more pupil dilation to threat-relevant stimuli compared to the neutral figural elements, and to trauma-exposed controls. Arousal-related pupil dilation significantly predicted PTSD after time elapsed since trauma, cumulative violence exposure, and trait anxiety were statistically controlled. The logistic regression model correctly classified 95% of the sample. Pupil reactivity shows promise as a physiological marker for PTSD.

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