Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20years. One measure that is often used to evaluate the translational relevance of these models to ...human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review “two hit” models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review “two hit” models of gene×environment and environment×environment interactions in which PPI has been measured.
Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to ...changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines-signaling molecules made in mitochondria-that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.
We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.
We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.
Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.
Increasing evidence indicates that inflammation plays a role in PTSD and stress disorder pathophysiology. PTSD is consistently associated with higher circulating inflammatory protein levels. Rodent ...models demonstrate that inflammation promotes enduring avoidance and arousal behaviors after severe stressors (e.g., predator exposure and social defeat), suggesting that inflammation may play a mechanistic role in trauma disorders. C‐reactive protein (CRP) is an innate acute phase reactant produced by the liver after acute infection and chronic disease. A growing number of investigations report associations with PTSD diagnosis and elevated peripheral CRP, CRP gene mutations, and CRP gene expression changes in immune signaling pathways. CRP is reasonably established as a potential marker of PTSD and trauma exposure, but if and how it may play a mechanistic role is unclear. In this review, we discuss the current understanding of immune mechanisms in PTSD with a particular focus on the innate immune signaling factor, CRP. We found that although there is consistent evidence of an association of CRP with PTSD symptoms and risk, there is a paucity of data on how CRP might contribute to CNS inflammation in PTSD, and consequently, PTSD symptoms. We discuss potential mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other innate immune signaling factors in modulating trauma responses. Overall, we found that CRP likely contributes to central inflammation, but how it does so is an area for further study.
This review describes our current understanding of how C‐reactive protein (CRP), potentially contributes mechanistically to PTSD pathology. We discuss the mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other immune signaling factors in modulating trauma responses. Overall, the evidence suggests that CRP can contribute to central inflammation, but how it does so is an area for further study.
Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring ...together academic, industrial, and governmental bodies to address this great 'unmet therapeutic need', the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains. In order to move the field forward and outline an approach for translational research, there is a need for a "preclinical MATRICS" to develop a rodent test battery that is appropriate for drug development. In this review, we outline such an approach and review current rodent tasks that target these seven domains of cognition. The rodent tasks are discussed in terms of their validity for probing each cognitive domain as well as a brief overview of the pharmacology and manipulations relevant to schizophrenia for each task.
Abstract
Background and Hypotheses
Social dysfunction in schizophrenia includes symptoms of withdrawal and deficits in social skills, social cognition, and social motivation. Based on the course of ...illness, with social withdrawal occurring prior to psychosis onset, it is likely that the severity of social withdrawal/isolation contributes to schizophrenia neuropathology.
Study Design
We review the current literature on social isolation in rodent models and provide a conceptual framework for its relationship to social withdrawal and neural circuit dysfunction in schizophrenia. We next review preclinical tasks of social behavior used in schizophrenia-relevant models and discuss strengths and limitations of existing approaches. Lastly, we consider new effort-based tasks of social motivation and their potential for translational studies in schizophrenia.
Study Results
Social isolation rearing in rats produces profound differences in behavior, pharmacologic sensitivity, and neurochemistry compared to socially reared rats. Rodent models relevant to schizophrenia exhibit deficits in social behavior as measured by social interaction and social preference tests. Newer tasks of effort-based social motivation are being developed in rodents to better model social motivation deficits in neuropsychiatric disorders.
Conclusions
While experimenter-imposed social isolation provides a viable experimental model for understanding some biological mechanisms linking social dysfunction to clinical and neural pathology in schizophrenia, it bypasses critical antecedents to social isolation in schizophrenia, notably deficits in social reward and social motivation. Recent efforts at modeling social motivation using effort-based tasks in rodents have the potential to quantify these antecedents, identify models (eg, developmental, genetic) that produce deficits, and advance pharmacological treatments for social motivation.
Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against ...nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.
Oxidative stress, in response to the activation of the superoxide-producing enzyme Nox2, has been implicated in the schizophrenia-like behavioral dysfunction that develops in animals that were ...subject to either neonatal NMDA receptor-antagonist treatment or social isolation. In both of these animal models of schizophrenia, an environmental insult occurring during the period of active maturation of the fast-spiking parvalbumin-positive (PV+) interneuronal circuit leads to a diminished expression of parvalbumin in GABA-inhibitory neurons when animals reach adulthood. The loss of PV+ interneurons in animal models had been tentatively attributed to the death of these neurons. However, present results show that for the perinatal NMDA-R antagonist model these interneurons are still alive when animals are 5–6 weeks of age even though they have lost their phenotype and no longer express parvalbumin. Alterations in parvalbumin expression and sensory-evoked gamma-oscillatory activity, regulated by PV+ interneurons, are consistently observed in schizophrenia. We propose that cortical networks consisting of faulty PV+ interneurons interacting with pyramidal neurons may be responsible for the aberrant oscillatory activity observed in schizophrenia. Thus, oxidative stress during the maturation window for PV+ interneurons by alteration of normal brain development, leads to the emergence of schizophrenia-like behavioral dysfunctions when subjects reach early adulthood.
This article is part of a Special Issue entitled ‘Schizophrenia’.
► Selective and non-selective NMDA receptor antagonists increase superoxide in adult brain. ► Early-life redox dysregulation induces schizophrenia-like neurochemical disruptions. ► Nox2-gene disruption prevents perinatal ketamine-induced loss of PV expression. ► Although parvalbumin-less, neurons remain alive after early-life manipulations
Mutant mouse models related to schizophrenia have been based primarily on the pathophysiology of schizophrenia, the known effects of antipsychotic drugs, and candidate genes for schizophrenia. ...Sensorimotor gating deficits in schizophrenia patients, as indexed by measures of prepulse inhibition of startle (PPI), have been well characterized and suggested to meet the criteria as a useful endophenotype in human genetic studies. PPI refers to the ability of a non-startling “prepulse” to inhibit responding to the subsequent startling stimulus or “pulse.” Because of the cross-species nature of PPI, it has been used primarily in pharmacological animal models to screen putative antipsychotic medications. As techniques in molecular genetics have progressed over the past 15 years, PPI has emerged as a phenotype used in assessing genetic mouse models of relevance to schizophrenia. In this review, we provide a selected overview of the use of PPI in mouse models of schizophrenia and discuss the contribution and usefulness of PPI as a phenotype in the context of genetic mouse models. To that end, we discuss mutant mice generated to address hypotheses regarding the pathophysiology of schizophrenia and candidate genes (i.e., hypothesis driven). We also briefly discuss the usefulness of PPI in phenotype-driven approaches in which a PPI phenotype could lead to “bottom up” approaches of identifying novel genes of relevance to PPI (i.e., hypothesis generating).
Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial ...infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes.
The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams.
Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations.
These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.
•Maternal immune activation (MIA) impaired probabilistic reversal learning.•MIA impaired social behavior.•MIA altered frontal cortex expression of potassium ion channel activity genes.•MIA altered expression of glutamatergic neurotransmission and mTOR signaling genes.•Hst1h2bc, Rictor and Rpl29 expression correlate with sociality and reversal learning.
•Animal models support role for peripheral and central immune signaling in anxiety/fear behavior.•Futures studies must address how specific immune mechanisms contribute to PTSD risk.•Future studies ...must address the effects of single vs multiple traumas on immune function and anxiety.
Mechanisms underlying posttraumatic stress disorder (PTSD) are not well understood; however, a potential role for immune signaling has recently emerged. Although PTSD is consistently associated with inflammatory markers, a causal role of immune signaling in symptom development is not clear. Here we present the most recent evidence for inflammatory dysfunction both preceding and following PTSD, and current evidence for immune-pathway contributions in animal models of PTSD. We address the role of peripheral vs. central immune signaling, single vs. chronic stress models of PTSD, and use of animal models to investigate novel anti-inflammatory treatments. Gaps in the literature including models of TBI/PTSD comorbidity, peripheral markers of inflammation, and inflammatory trajectories after severe stress are discussed.
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