Learning From Animal Models of Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) affects 2%-3% of the population worldwide and can cause significant distress and disability. Substantial challenges remain in the field of OCD research and therapeutics. Approved interventions alleviate symptoms only partially, with 30%-40% of patients being resistant to treatment. Although the etiology of OCD is still unknown, research evidence points toward the involvement of cortico-striato-thalamocortical circuitry. This review focuses on the most recent behavioral, genetics, and neurophysiologic findings from animal models of OCD. Based on evidence from these models and parallels with human studies, we discuss the circuit hyperactivity hypothesis for OCD, a potential circuitry dysfunction of action termination, and the involvement of candidate genes. Adding a more biologically valid framework to OCD will help researchers define and test new hypotheses and facilitate the development of targeted therapies based on disease-specific mechanisms

Modeling psychiatric disorders for developing effective treatments

Recent advances in identifying risk-associated genes have provided unprecedented opportunities for developing animal models for psychiatric disease research with the goal of attaining translational utility to ultimately develop novel treatments. However, at this early stage, successful translation has yet to be achieved. Here we review recent advances in modeling psychiatric disease, discuss the utility and limitations of animal models, and emphasize the importance of shifting from behavioral analysis to identifying neurophysiological abnormalities, which are likely to be more conserved across species and thus may increase translatability. Looking forward, we envision that preclinical research will align with clinical research to build a common framework of comparable neurobiological abnormalities and to help form subgroups of patients on the basis of similar pathophysiology. Experimental neuroscience can then use animal models to discover mechanisms underlying distinct abnormalities and develop strategies for effective treatments.National Institute of Mental Health (U.S.) (Grant 5R01MH097104

SHANK proteins: roles at the synapse and in autism spectrum disorder

Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviourResearch related to this work in the laboratory of G.F. is supported by the Poitras Center for Affective Disorders Research at the Massachusetts Institute of Technology (MIT), Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, National Institute of Mental Health (MH097104), Nancy Lurie Marks Family Foundation, Simons Foundation Autism Research Initiative (SFARI grant 178130) and Simons Center for the Social Brain at MIT. P.M. is supported by Society in Science, The Branco Weiss Fellowship, administered by Eidgenössische Technische Hochschule (ETH) Zürich, and European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 89–2016)info:eu-repo/semantics/publishedVersio

Transgenic mouse models of childhood-onset psychiatric disorders

Available in PMC 2012 April 1.Childhood-onset psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, obsessive compulsive spectrum disorders (OCSD), and schizophrenia (SZ), affect many school-age children, leading to a lower quality of life, including difficulties in school and personal relationships that persist into adulthood. Currently, the causes of these psychiatric disorders are poorly understood, resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, mood disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Transgenic mouse models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single mouse model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing transgenic mouse models for childhood-onset psychiatric disorders. We compare the strength and weakness of various transgenic mouse models proposed for each of the common childhood-onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools.National Institutes of Health (U.S.) (postdoctoral training program fellowship)National Institute of Mental Health (U.S.)Hartwell FoundationSimons FoundationMcKnight FoundationDuke Institute for Brain Science

Recombineering strategies for developing next generation BAC transgenic tools for optogenetics and beyond

The development and application of diverse BAC transgenic rodent lines has enabled rapid progress for precise molecular targeting of genetically-defined cell types in the mammalian central nervous system. These transgenic tools have played a central role in the optogenetic revolution in neuroscience. Indeed, an overwhelming proportion of studies in this field have made use of BAC transgenic Cre driver lines to achieve targeted expression of optogenetic probes in the brain. In addition, several BAC transgenic mouse lines have been established for direct cell-type specific expression of Channelrhodopsin-2 (ChR2). While the benefits of these new tools largely outweigh any accompanying challenges, many available BAC transgenic lines may suffer from confounds due in part to increased gene dosage of one or more “extra” genes contained within the large BAC DNA sequences. Here we discuss this under-appreciated issue and propose strategies for developing the next generation of BAC transgenic lines that are devoid of extra genes. Furthermore, we provide evidence that these strategies are simple, reproducible, and do not disrupt the intended cell-type specific transgene expression patterns for several distinct BAC clones. These strategies may be widely implemented for improved BAC transgenesis across diverse disciplines.Brain and Behavior Research Foundation (Young Investigator Award)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F32-MH084460

Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition estimated to afflict 1-3% of the world population. The estimated financial impact in the treatment and management of OCD is in the billions of dollars annually in the US alone. At present there is a marked lack of evidence on the specific causes of OCD. Current hypotheses largely focus on the serotonin (5-HT) system on the basis of the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in alleviating symptoms of patients with OCD, yet a considerable fraction of patients are non-responsive or minimally responsive to these agents. Despite this fact, SSRIs have remained the primary pharmacological treatment avenue for OCD. In recent years, multiple lines of evidence have implicated glutamatergic synaptic dysfunction within the cortico-striatal-thalamo-cortical (CSTC) brain circuit in the etiology of OCD and related disorders, thereby prompting intensified effort in the development and evaluation of agents that modulate glutamatergic neurotransmission for the treatment of OCD. With this in mind, here we review the following topics with respect to synaptic dysfunction and the neural circuitry underlying OCD: (1) evidence supporting the critical involvement of the CSTC circuit, (2) genetic studies supporting the involvement of glutamatergic dysfunction, (3) insights from genetic animal models of OCD, and (4) preliminary findings with glutamatergic neurotransmission-modulating agents in the treatment of OCD. Given the putative mechanistic overlap between OCD and the broader OC-spectrum of disorders, unraveling the synaptic basis of OCD has potential to translate into more effective treatments for an array of poorly understood human disorders

A viral strategy for targeting and manipulating interneurons across vertebrate species

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.National Institutes of Health (U.S.) (Grant MH071679)National Institutes of Health (U.S.) (Grant NS08297)National Institutes of Health (U.S.) (Grant NS074972)National Institutes of Health (U.S.) (Grant MH095147)National Institutes of Health (U.S.) (Grant MH066912)National Institutes of Health (U.S.) (Grant EY022577)National Institutes of Health (U.S.) (Grant MH063912