Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

/pdf/animal-models-of-neuropsychiatric-disorders-1w7jb15e05.pdf

Animal models of neuropsychiatric disorders

Scientists in many different fields have been attracted to the study of habits because of the power habits have over behavior and because they invoke a dichotomy between the conscious, voluntary control over behavior, considered the essence of higher-order deliberative behavioral control, and lower-order behavioral control that is scarcely available to consciousness. A broad spectrum of behavioral routines and rituals can become habitual and stereotyped through learning. Others have a strong innate basis. Repetitive behaviors can also appear as cardinal symptoms in a broad range of neurological and neuropsychiatric illness and in addictive states. This review suggests that many of these behaviors could emerge as a result of experience-dependent plasticity in basal ganglia–based circuits that can influence not only overt behaviors but also cognitive activity. Culturally based rituals may reflect privileged interactions between the basal ganglia and cortically based circuits that influence social, emotional...

Habits, Rituals, and the Evaluative Brain

Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100–150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.

/pdf/behavioural-phenotyping-assays-for-mouse-models-of-autism-4x4zr45d44.pdf

Behavioural phenotyping assays for mouse models of autism

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice. Autism and autism spectrum disorders (ASDs) are neurodevelopmental disorders diagnosed based on a triad of criteria: deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviours 1 . ASDs are highly heritable disorders with concordance rates as high as 90% for monozygotic twins 2 . Recent genetic and genomic studies have identified a large number of candidate genes for ASDs 3 , many of which encode synaptic proteins 4–6 , indicating synaptic dysfunction may have a critical role in ASDs 7,8 . One of the most promising ASD candidate genes is Shank3, which codes for a key postsynaptic density (PSD) protein at glutamatergic synapses. Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan–McDermid syndrome), an autism spectrum disorder 9–11 . Furthermore, recent genetic screens have identified several mutations/rare variants of the Shank3 gene in ASD patients outside of diagnosed 22q13 deletion syndrome 12,13 . The Shank family of proteins (SHANK1–3) directly bind SAPAP (also known as DLGAP) to form the PSD-95–SAPAP–SHANK complex 14,15 (PSD-95 is also known as DLG4). This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signalling complex at glutamatergic synapses. Currently, however, little is known about the in vivo function of SHANK3 at the synapse and how a disruption of Shank3 may contribute to ASDs. Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASDs. Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at corticostriatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs. Our studies provide a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviours. Shank3B 2/2 mice display repetitive grooming

/pdf/shank3-mutant-mice-display-autistic-like-behaviours-and-kc224hjlsp.pdf

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Striatal plasticity and basal ganglia circuit function.

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours.

/pdf/cortico-striatal-synaptic-defects-and-ocd-like-behaviours-in-bvx9j3535x.pdf

Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3 -mutant mice

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Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3 -mutant mice