Sensorimotor Gating Abnormalities Research Articles

Possible involvement of Interleukin-17A in the deterioration of prepulse inhibition on acoustic startle response in mice.

Proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL-17A, induces impairment in sensorimotor gating in mice. We also examined whether IL-17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub-chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL-17A administration. We evaluated the effect of IL-17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Administration of IL-17A induced significant PPI deterioration. Low-dose of IL-17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low-dose IL-17A administration group. We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption and that IL-17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL-17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.

Prenatal ketamine exposure impairs prepulse inhibition via arginine vasopressin receptor 1A-mediated GABAergic neuronal dysfunction in the striatum

Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.

Overexpression of transmembrane TNFα in brain endothelial cells induces schizophrenia-relevant behaviors.

Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder.

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD‐93 protein reduction) a novel clinically relevant Dlg2 +/− rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N‐Methyl‐D‐aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD‐93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 +/− rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 +/− mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

Prenatal disruption of D1R-SynGAP complex causes cognitive deficits in adulthood

γ-aminobutyric acid (GABA)-ergic interneurons are essential for the physiological function of the mammalian central nervous system. Dysregulated GABAergic interneuron function has been implicated in the pathophysiology of a number of neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Tangential migration is an important process to ensure the proper localization of GABAergic interneurons. Previously we found that disrupting the interaction between dopamine D1 receptor (D1R) and synaptic Ras GTPase- activating protein (SynGAP) using an interfering peptide (TAT-D1Rpep) during embryonic development impaired tangential migration. Here, we assessed the effects of prenatal disruption of D1R-SynGAP complex with the TAT-D1Rpep on the expression of several behaviours during adulthood. Mice with prenatal D1R-SynGAP disruption exhibited transiently reduced locomotor activity, abnormal sensorimotor gating, impaired sociability and deficits in visual discrimination associative learning compared to their control counterparts. Our findings reinforce the importance of GABAergic interneuron migration in the manifestation of normal motor, sensory, and cognitive behaviours of animals during adulthood.

M102. MEASURING PHYSIOLOGICAL RESPONSES ASSOCIATED WITH SOCIAL STRESS IN A VIRTUAL ENVIRONMENT AND ITS RELATIONSHIP WITH CHILDHOOD TRAUMA IN EARLY SCHIZOPHRENIA - A PILOT STUDY

BackgroundIn lower to middle income countries (LMIC), the influences of environmental stress on neurobiological processes involved in the development of schizophrenia is of great importance. High levels of stress may contribute to an increased burden of schizophrenia, including profound functional impairment and disability, decreased productivity, and even elevated mortality. Stress in Schizophrenia has been associated with behavioral disturbances such as maladaptive coping styles as well as well-established physiological abnormalities in sensorimotor gating in the form of abnormal startle responses. In turn, childhood trauma exposure is known to affect physiological stress responses. Indeed, we have found childhood trauma to be associated with both white matter and hippocampal changes in schizophrenia. Few studies, however, have explored the relationship between Childhood trauma and stress responses in schizophrenia. In recent years Virtual Reality (VR) has undergone a resurgence as a viable method for studying fear related physiological stress responses in an ecologically valid manner. Here we aim to investigate the potential relationship between abnormal physiological stress responses in schizophrenia with early life adversity.MethodsPhysiological response data were collected while participants completed a VR paradigm based on the Trier stress test, a well-established social stressor that reliably elicits a stress response in participants in VR and HPA axis attenuation in schizophrenia. Data were also collected in a fear of heights environment, not associated with abnormalities in schizophrenia. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). HPA axis stress responses during the course of the task were assessed using saliva cortisol samples collected at key points during the paradigms.ResultsPreliminary data of both the social anxiety and fear of heights scenario will be presented. We will focus specifically on the viability of using VR in a LMIC context.DiscussionVR could prove to be a cost-effective tool to explore the relationship between childhood trauma, stress sensitivity and schizophrenia.

The Schizophrenia Susceptibility Gene OPCML Regulates Spine Maturation and Cognitive Behaviors through Eph-Cofilin Signaling

Previous genetic and biological evidence converge on the involvement of synaptic dysfunction in schizophrenia, and OPCML, encoding a synaptic membrane protein, is reported to be genetically associated with schizophrenia. However, its role in the pathophysiology of schizophrenia remains largely unknown. Here, we found that Opcml is strongly expressed in the mouse hippocampus; ablation of Opcml leads to reduced phosphorylated cofilin and dysregulated F-actin dynamics, which disturbs the spine maturation. Furthermore, Opcml interacts with EphB2 to control the stability of spines by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml-deficient mice display impaired cognitive behaviors and abnormal sensorimotor gating, which are similar to features in neuropsychiatric disorders such as schizophrenia. Notably, the administration of aripiprazole partially restores the abnormal behaviors in Opcml-/- mice by increasing the phosphorylated cofilin level and facilitating spine maturation. We demonstrated a critical role of the schizophrenia-susceptible gene OPCML in spine maturation and cognitive behaviors via regulating the ephrin-EphB2-cofilin signaling pathway, providing further insights into the characteristics of schizophrenia.

Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association with Memory and Social Impairments and Abnormal Sensorimotor Gating

BackgroundEvidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association.MethodsWe analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system.ResultsMCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating.ConclusionsOur study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia.

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response

Sensory processing abnormalities are consistently associated with autism, but the underlying mechanisms and treatment options are unclear. Fragile X Syndrome (FXS) is the leading known genetic cause of intellectual disabilities and autism. One debilitating symptom of FXS is hypersensitivity to sensory stimuli. Sensory hypersensitivity is seen in both humans with FXS and FXS mouse model, the Fmr1 knock out (Fmr1 KO) mouse. Abnormal sensorimotor gating may play a role in the hypersensitivity to sensory stimuli. Humans with FXS and Fmr1 KO mice show abnormalities in acoustic startle response (ASR) and prepulse inhibition (PPI) of startle, responses commonly used to quantify sensorimotor gating. Recent studies have suggested high levels of matrix metalloproteinase-9 (MMP-9) as a potential mechanism of sensory abnormalities in FXS. Here we tested the hypothesis that genetic reduction of MMP-9 in Fmr1 KO mice rescues ASR and PPI phenotypes in adult Fmr1 KO mice. We measured MMP-9 levels in the inferior colliculus (IC), an integral region of the PPI circuit, of WT and Fmr1 KO mice at P7, P12, P18, and P40. MMP-9 levels were higher in the IC of Fmr1 KO mice during early development (P7, P12), but not in adults. We compared ASR and PPI responses in young (P23-25) and adult (P50-80) Fmr1 KO mice to their age-matched wildtype (WT) controls. We found that both ASR and PPI were reduced in the young Fmr1 KO mice compared to age-matched WT mice. There was no genotype difference for ASR in the adult mice, but PPI was significantly reduced in the adult Fmr1 KO mice. The adult mouse data are similar to those observed in humans with FXS. Genetic reduction of MMP-9 in the Fmr1 KO mice resulted in a rescue of adult PPI responses to WT levels. Taken together, these results show sensorimotor gating abnormalities in Fmr1 KO mice, and suggest the potential for MMP-9 regulation as a therapeutic target to reduce sensory hypersensitivity.

Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice

Recently, numerous rare de novo mutations have been identified in patients diagnosed with autism spectrum disorders (ASD). However, despite the predicted loss-of-function nature of some of these de novo mutations, the affected individuals are heterozygous carriers, which would suggest that most of these candidate genes are haploinsufficient and/or lead to expression of dominant-negative forms of the protein. Here, we tested this hypothesis with the candidate ASD gene Nuak1 that we previously identified for its role in the development of cortical connectivity. We report that Nuak1 is haploinsufficient in mice with regard to its function in cortical development. Furthermore Nuak1+/− mice show a combination of abnormal behavioral traits ranging from defective spatial memory consolidation, defects in social novelty (but not social preference) and abnormal sensorimotor gating. Overall, our results demonstrate that Nuak1 haploinsufficiency leads to defects in the development of cortical connectivity and a complex array of behavorial deficits.

Systemic Treatment with the Enteric Bacterial Fermentation Product, Propionic Acid, Reduces Acoustic Startle Response Magnitude in Rats in a Dose-Dependent Fashion: Contribution to a Rodent Model of ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by cognitive and sensorimotor deficits, among others. Hypo-sensitivity and hyper-sensitivity to different stimuli within the same sensory modality, a prominent symptom of ASD, can be assessed by acoustic startle response (ASR) and prepulse inhibition (PPI). Propionic acid (PPA) is a short-chain fatty acid and a by-product of the human gut microbiome. Rodents treated with PPA has been found to produce ASD-related behavioral abnormalities, gastrointestinal discomfort, and conditioned aversions. The present study examined ASR and PPI in adult male rats treated systemically (intraperitoneal injections) with two different doses of PPA. A single injection of PPA produced significant dose-dependent reductions in startle response magnitude relative to control rats. However, PPA-treated rats did not show significant sensorimotor gating abnormalities relative to controls, based on the PPI measures. These findings add to the growing body of evidence supporting the validity of the PPA rodent model of ASD.

The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function.

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.

Sensorimotor gating deficits are inheritable in an isolation-rearing paradigm in rats

Early life experience is a key etiological factor of neuropsychiatric dysfunctions and is associated with developmental origins. Impaired prepulse inhibition (PPI) following an acoustic startle response is acknowledged as a cardinal characteristic in socially deprived weanling rats, which has been employed to investigate the underlying mechanisms of sensorimotor gating abnormalities in certain mental disorders, including schizophrenia. Because impaired PPI is a postnatal malfunction, it is interesting to examine whether it can be passed to the next generation. Isolation-rearing (IR) rats had been socially deprived since weaning, which mated with social rearing rats. Next, the offspring of IR rats were reared in a normal social environment. Locomotion, PPI, monoamines, and genes in schizophrenia-relevant brain areas [medial prefrontal cortex (mPFC) and hippocampus] were later measured. To this end, we observed that the next generation of IR offspring rats appeared with impaired PPI in which the PPI deficit can be observed as early as three weeks after birth. The third generation also exhibited lower levels of dopamine and serotonin in the mPFC and hippocampus; however, higher levels of both monoamines were measured in the striatum. Finally, Slc1a2 was more highly expressed in the mPFC of the third generation male rats. The present study demonstrates a transgenerational inheritance of IR-induced character and may help to elucidate the underlying pathoetiology of schizophrenia.

Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1.

Exploring drug targets based on disease-associated molecular mechanisms during development is crucial for the generation of novel prevention and treatment strategies for neurodevelopmental psychiatric conditions. We report that prefrontal cortex-specific postnatal knockdown of DISC1 via in utero electroporation combined with an inducible knockdown expression system drives deficits in synaptic GABAA function and dendritic development in pyramidal neurons, as well as abnormalities in sensorimotor gating, albeit without profound memory deficits. We show for the first time that DISC1 is specifically involved in regulating cell surface expression of α2 subunit-containing GABAA receptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with α2/3 subtype-selective GABAA receptor positive allosteric modulators during the early postnatal period ameliorates dendritic deficits and behavioral abnormalities induced by knockdown of DISC1. These findings highlight a critical role of DISC1-mediated disruption of postnatal GABA signaling in aberrant prefrontal cortex maturation and function.

Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.

Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.

The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior

Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases.

Effects of SPAK knockout on sensorimotor gating, novelty exploration, and brain area-dependent expressions of NKCC1 and KCC2 in a mouse model of schizophrenia.

SPAK (Sterile 20/SPS1-related proline/alanine-rich kinase) is a protein kinase belonging to the mitogen-activated protein kinase (MAPK) superfamily that has been found to be extensively distributed across the body. The SPAK downstream substrates NKCC1 and KCC2 in the central nervous system are important in the interpretation of developmental mental disorders. The present study aimed to clarify the role of SPAK-NKCC1/KCC2 using a rodent schizophrenia-like model. The mouse paradigm of isolation rearing (IR) was employed, as it simulates the sensorimotor gating abnormalities of schizophrenia. SPAK transgenic mice were used and were divided into four groups: social-wild type, social-SPAK(-/-), isolation-wild type, and isolation-SPAK(-/-). The prepulse inhibition (PPI) test and the novel object recognition test (NORT) were used to measure schizophrenia-associated dysfunctions in gating ability and the novelty recognition, respectively. Finally, the protein expressions of NKCC1/KCC2 in the prefrontal cortex and hippocampus were detected to determine correlations with the behavioral data. Our results demonstrated that SPAK-null mice had superior PPI and novelty recognition relative to wild type controls, with a concomitant increase in KCC2 in the prefrontal cortex. IR disrupted PPI and NORT performances with an associated increase in KCC2. Furthermore, rearing environment and gene manipulation had mutually interactive effects, as the IR-induced effects on PPI and NORT were reversed by SPAK knockout, and the increase in KCC2 and the decreased in the NKCC1/KCC2 ratio in the prefrontal cortex induced by SPAK knockout were reversed by IR. Our data supported the gene-environment hypothesis and demonstrated the potential value of SPAK manipulation in future schizophrenia studies.

Prenatal Exposure to the Viral Mimetic Poly I:C Alters Fetal Brain Cytokine Expression and Postnatal Behaviour

An increased incidence of mental illness disorders is found in children and adolescents born to mothers who experienced an infection-based illness during pregnancy. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents, which are immature (altricial) at birth compared with the human neonate. In this study, we used the precocial spiny mouse (Acomys cahirinus), whose offspring have completed organogenesis at birth, and administered a single subcutaneous injection of a 5 mg/kg dose of the viral mimetic poly I:C (polyriboinosinic-polyribocytidylic acid) at mid gestation (20 days; term is 39 days). Prenatal exposure to poly I:C caused a transient weight loss in the pregnant dam, produced a downregulation of the proinflammatory cytokine tumour necrosis factor-α in the fetal brain, and resulted in abnormalities in sensorimotor gating and reduced social interaction, memory and learning in juvenile offspring. No changes in exploratory activity or anxiety and fear behaviours were found between the treatment groups. This study provides evidence that, in a rodent model that more closely resembles human brain development, prenatal infection can lead to behavioural abnormalities in postnatal life.

Effects of MK-801 treatment across several pre-clinical analyses including a novel assessment of brain metabolic function utilizing PET and CT fused imaging in live rats

BackgroundFunctional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. MethodsThe validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days. ResultsAcute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. LimitationsWhile PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions. ConclusionThese findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.