What Causes Obsessive Compulsive Disorder?: Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by Rauch and Carlezon Jr. ). Ahmari et al. (p. 1234 ) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine. Burguière et al. (p. 1243 ) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming.

Re-expression of the Shank3 gene in adult mice results in improvements in synaptic protein composition and spine density in the striatum; Shank3 also rescues autism-like features such as social interaction and grooming behaviour, and the results suggest that aspects of autism spectrum disorders may be reversible in adulthood. Mutations in the Shank3 gene have been linked to autism, and mice lacking Shank3 expression display features of autism, including social deficits, anxiety and repetitive behaviour, as well as defects in striatal synapses. Guoping Feng and colleagues now show that re-expression of Shank3 in adult mice reversed the synaptic changes and increased spine density in the striatum. It also selectively rescued social interaction and grooming behaviour — two core features of autism — whereas anxiety and motor impairments could only be prevented by Shank3 re-expression during development. These findings show that Shank3 expression can affect neural function post-development, and suggest that aspects of autism spectrum disorder pathology may be reversible in adulthood. Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three1, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases2,3,4,5,6. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex7,8,9. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour10,11,12,13. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.

Increasing evidence implicates abnormalities in corticostriatal circuits in the pathophysiology of obsessive-compulsive disorder (OCD) and OC-spectrum disorders. Parallels between the emergence of repetitive, compulsive behaviors and the acquisition of automated behaviors suggest that the expression of compulsions could in part involve loss of control of such habitual behaviors. The view that striatal circuit dysfunction is involved in OC-spectrum disorders is strengthened by imaging and other evidence in humans, by discovery of genes related to OCD syndromes, and by functional studies in animal models of these disorders. We highlight this growing concordance of work in genetics and neurobiology suggesting that frontostriatal circuits, and their links with basal ganglia, thalamus and brainstem, are promising candidates for therapeutic intervention in OCD.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a wide spectrum of symptoms, mainly characterized by social, communication, and cognitive impairments. Latest diagnostic criteria according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013) now include sensory issues among the four restricted/repetitive behavior features defined as “hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment”. Here, we review auditory sensory alterations in patients with ASD. Considering the updated diagnostic criteria for ASD, we examined research evidence (2015–2022) of the integrity of the cognitive function in auditory-related tasks, the integrity of the peripheral auditory system, and the integrity of the central nervous system in patients diagnosed with ASD. Taking into account the different approaches and experimental study designs, we reappraise the knowledge on auditory sensory alterations and reflect on how these might be linked with behavior symptomatology in ASD.