Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.

A signaling pathway AKTing up in schizophrenia.

The serine/threonine protein kinase AKT (also known as PKB) signaling pathway has been associated with several human diseases, including schizophrenia. Studies in preclinical models have demonstrated that impaired AKT signaling affects neuronal connectivity and neuromodulation and have identified AKT as a key signaling intermediary downstream of dopamine (DA) receptor 2 (DRD2), the best-established target of antipsychotic drugs. A study by Tan et al. in this issue of the JCI strengthens links among AKT signaling, DA transmission, and cognition in healthy individuals and offers potential avenues to explore in an effort to find more effective pharmacotherapies for schizophrenia and related disorders (see the related article beginning on page 2200).

A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.

Modeling madness in mice: one piece at a time.

Mouse models that recapitulate the full phenotypic spectrum of a psychiatric disorder, such as schizophrenia, are impossible. However, a more piecemeal recreation of phenotypic components is feasible and promises to harness the power of animal models using approaches that are either off limits or confounded by drug treatment in humans. In that context, animal models will have a central and indispensable role in the process of discovering the causes of psychiatric disorders and generating novel, mechanism-based treatments. Here, we discuss current approaches used to generate animal models of psychiatric disorders, address the different components of these disorders that can be modeled in animals, and describe currently available analytical tools. We also discuss accumulating empirical data and take an in-depth look at what we believe to be the future of animal models made possible by recent advances in psychiatric genetics.

Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium.

In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.

Null mutation of the arginine-vasopressin gene in rats slows attentional engagement and facilitates response accuracy in a lateralized reaction time task.

The neurophysin vasopressin is thought to play an important role in emotional behavior and aspects of cognition in the rat, and the pathophysiology of this system has been implicated in two neurodevelopmental disorders, namely autism and schizophrenia. Genetic deficiency of vasopressin in rats, resulting from a null mutation of the vasopressin gene, causes alterations of brain development with resulting behavioral and neurochemical phenotypes in adulthood. We previously demonstrated that partial vasopressin deficiency (rats heterozygous for the null mutation) produces enhanced visuospatial attention and motor speeding. Here, the results of studies of homozygous Brattleboro rats that are fully vasopressin deficient are reported. We trained subjects to perform a lateralized reaction time task that measures visuospatial divided attention; in task conditions in which the duration of target stimuli was varied from trial to trial, homozygous Brattleboro rats showed a performance phenotype that consisted of more accurate responding for longer duration, and less accurate responding for briefer duration, target stimuli. No differences in response times were measured. Further experiments revealed that two separate processes produced this complex phenotype: a relatively slowed period of attentional engagement (resulting in compromised detection of fast onset-fast offset stimuli) that only partially masks a generally more accurate pattern of responding. These results, taken with earlier data, indicate that vasopressin plays a critical role in regulating visual attention and cognition, either directly, or via early alterations in neurodevelopment.

Cannabinoid CB1 receptor-mediated impairment of visuospatial attention in the rat.

RATIONALE: CB1 receptors (CB1Rs) mediate many of the psychoactive effects of cannabinoids, and marijuana intoxication can produce neurocognitive deficits with a similarity to those seen in schizophrenia, including impairments of attention. OBJECTIVES: We thus sought to characterize the effects of a CB1R-selective agonist and antagonist on attention in the rat using a lateralized reaction time task (LRT). We hypothesized that CB1R agonists would impair performance and that CB1R antagonists might improve performance. METHODS: Subjects were trained to perform the LRT, a procedure that measured their ability to attend to and detect brief visual target stimuli. After training, we tested the effects of the CB1R agonist WIN55,212-2 (WIN; 0-2.5 mg/kg) or the CB1R antagonist SR141716A (SR; 0-1.0 mg/kg), administered alone or in combination, on visual attention performance using task conditions in which target stimulus salience was varied systematically across trials. RESULTS: The highest dose of WIN reduced correct choices in well-trained rats, with impairment greatest at the shortest stimulus durations. The highest dose of WIN also increased omissions and slowed response times. By contrast, SR itself did not produce any measurable effects on performance but was able to prevent the impairment produced by WIN. CONCLUSIONS: These results suggest that CB1Rs mediate the attentional performance impairments caused by acute administration of cannabinoid agonists and begin to unravel the possible contribution of cannabinoid systems to the pathophysiological substrates of cognitive dysfunction in schizophrenia.

Genetic and cognitive windows into circuit mechanisms of psychiatric disease.

Accumulating evidence indicates substantial etiological and pathophysiological heterogeneity as well as overlap within and across psychiatric disorders. Moreover, it is uncertain at what level, besides gross behavior, mental illnesses can be differentiated. To advance our understanding of psychiatric disease, we advocate a more systematic approach in characterizing a small number of animal models by utilizing unequivocal rare disease mutations and targeted cognitive assessment to identify convergent disease circuits and mechanisms. Based on available data, we discuss the possibility that the temporal dynamics of synaptic plasticity play a central role in disease pathophysiology and that the extent and manner in which they are altered in specific neural circuits determine the exact clinical phenotype of diverse disorders.

Cognition in mouse models of schizophrenia susceptibility genes.

Cognitive deficits are core features of psychiatric disorders and contribute substantially to functional outcome. It is still unclear, however, how cognitive deficits are related to underlying genetic liability and overt clinical symptoms. Fortunately, animal models of susceptibility genes can illuminate how the products of disease-associated genetic variants affect brain function and ultimately alter behavior. Using as a reference findings from the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia program and the SchizophreniaGene database, we review cognitive data from mutant models of rare and common genetic variants associated with schizophrenia.

Development of animal models for schizophrenia.

Schizophrenia is a devastating psychiatric disorder that affects around 1% of the population worldwide. The disease is characterized by 'positive symptoms', 'negative symptoms' and cognitive deficits. Over the last 60 years, a large number of family, twin and adoption studies have clearly demonstrated a strong genetic component for schizophrenia, but the mode of inheritance of the disease is complex and, in all likelihood, involves contribution from multiple genes in conjunction with environmental and stochastic factors. Recently, several genome-wide scans have demonstrated that rare alleles contribute significantly to schizophrenia risk. Assessments of rare variants have identified specific and probably causative, disease-associated structural mutations or copy number variants (CNVs, which result from genomic gains or losses). The fact that the effects of such lesions are transparent allows the generation of etiologically valid animal models and the opportunity to explore the molecular, cellular and circuit-level abnormalities underlying the expression of psychopathology. To date, the most common genomic structural rearrangements that are unequivocally associated with the development of schizophrenia, are de novo microdeletions of the 22q11.2 locus. Fortunately, the human 22q11.2 locus is conserved within the syntenic region of mouse chromosome 16, which harbors nearly all orthologues of the human genes. This has made it possible to engineer genetically faithful, and thus etiologically valid, animal models of this schizophrenia susceptibility locus.

Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice.

Disrupted-In-Schizophrenia (DISC1) is a leading candidate schizophrenia susceptibility gene. Here, we describe a deletion variant in mDisc1 specific to the 129S6/SvEv strain that introduces a termination codon at exon 7, abolishes production of the full-length protein, and impairs working memory performance when transferred to the C57BL/6J genetic background. Our findings provide insights into how DISC1 variation contributes to schizophrenia susceptibility in humans and the behavioral divergence between 129S6/SvEv and C57BL/6J mouse strains and have implications for modeling psychiatric diseases in mice.