Sensorimotor Gating Deficits Research Articles

S181. ANALYSIS OF THE AMELIORATING EFFECT OF D-SERINE ON GLUN2D DEFICIENT MICE

BackgroundThe glutamate hypothesis of schizophrenia postulates NMDA receptor (NMDAR) hypofunction as a major pathophysiological mechanism based on clinical observations and preclinical evidence. Mice with globally reduced NMDAR expression display hyperlocomotion, sensorimotor gating deficits, cognitive deficits and social withdrawal. NMDARs are tetramers composed of 2 obligatory GluN1 (NR1) and 2 variable GluN2A-D (NR2A-D) subunits. GluN2A and GluN2B are the main cortical NMDAR subunits, but genetic models provided evidence that psychosis-like effects of NMDAR antagonists are mediated by GluN2C/GluN2D subunits. Previous data suggest a role also of the GluN2D subunit in schizophrenia-associated abnormalities [1].MethodsWe aimed to assess a comprehensive behavioural phenotyping of GluN2D deficient mice, including locomotion, affective behaviours and general welfare, but drew special focus on cognitive functions, including spatial learning, short-term and long-term memory, as well as puzzle solving. We further investigated the effect of D-Serine on the GluN2D KO mice. D-Serine is a NMDAR modulator and acts as an agonist at the glycine site. Previous work in clinical trials suggests significant therapeutic effects of D-serine on negative and positive symptoms, cognitive deficits and motor symptoms. We used the chronic application of D-Serin by supplementing it into the drinking water of the subjects.ResultsPreliminary data indicate no effect on locomotor alterations of the GluN2D mice, however a potential improvement in short-term memory and wellbeing-associated parameters. They indicate a role of the GluN2D subunit and a beneficial effect of D-serine on schizophrenia-induced parameters, including physiological, welfare-associated burrowing and cognitive performance in the short term task of the puzzle box test.DiscussionOur preliminary data indicate a role of the GluN2D subunit in the emergence of cognitive deficits associated with schizophrenia and a potential therapeutic effect of D-serine in alleviating these deficits. Further investigations are planned to further validate these findings.ReferenceInta et. al, Neurosci Biobehav Rev, 34(3): 285–94, 2010

Does genetic mouse model of constitutive Hint1 deficiency exhibit schizophrenia-like behaviors?

The histidine triad nucleotide binding protein 1 (HINT1) is closely related to many neuropsychiatric disorders. Clinical studies supported that mutations in the Hint1 gene correlated potentially with schizophrenia. In addition, Hint1 gene knockout (KO) mice exhibited hyperactivity induced by amphetamine and apomorphine. However, it is still unclear whether this animal model exhibits schizophrenia-like behaviors and, if so, their underlying mechanisms remain to be elucidated. Thus, our study sought to evaluate schizophrenia-like behaviors in Hint1-KO mice, and explore the associated changes in neuronal structural plasticity and schizophrenia-related molecules. A series of behavioral tests were used to compare Hint1-KO and their wild-type (WT) littermates, alongside a number of morphological and molecular biological methods. Relative to WT mice, Hint1-KO mice exhibited reduced social interaction behaviors, aggressive behavior, sensorimotor gating deficits, apathetic and self-neglect behaviors, and increased MK-801-induced hyperactivity. Hint1-KO mice also showed partly increased dendritic complexity in the hippocampus (Hip) relative to WT mice. Total glutamate was decreased in the medial prefrontal cortex, nucleus accumbens (NAc), and Hip of KO mice. Expression of NR1, NR2A, and D4R was decreased whereas that of D1R was increased in the NAc of KO relative to WT mice. The expression level of NR2B was increased whereas that of D1R was decreased in the Hip of KO mice. Hint1-KO mice exhibited schizophrenia-like behaviors. Partly increased dendritic complexity and dysfunction in both the dopaminergic and glutamatergic systems may be involved in the abnormalities in Hint1-KO mice.

T177. CANNABIDIOL AS A POTENTIAL PREVENTATIVE TREATMENT IN A NEUREGULIN-1 MOUSE MODEL OF SCHIZOPHRENIA

BackgroundSchizophrenia is caused by interactions between genes of predisposition and environmental insults. The main pharmacological treatments for schizophrenia are antipsychotic drugs; however, these are associated with a range of side effects (weight gain, metabolic disease, diabetes), have limited treatment compliance, and do not work for approximately 30% of patients. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise as an antipsychotic-like drug in both human and rodent studies, however its potential as a preventative drug via anti-inflammatory pathways has not yet been investigated. Brain maturation during adolescent development creates a window where CBD could potentially reverse later behavioural deficits via pathways such as anti-inflammation, and reverse the deficits caused by Δ⁹-tetrahydrocannabinol (THC), a psychoactive compound of the cannabis plant linked to the development of schizophrenia.Here we investigated the therapeutic potential of CBD administered in adolescence to protect against the development of schizophrenia-like behaviours, as well as whether CBD could protect against later sensitivity to THC. For this study we used a well-established genetic mouse model of schizophrenia (Nrg1 TM HET) that shows face, construct, and predictive validity for schizophrenia, and is also more susceptible to the effects of cannabinoids.MethodsIn this study, male Nrg1 TM HET mice and wild type (WT) mice were treated with 30 mg/kg of CBD or vehicle intraperitoneally for three weeks during adolescence (PND 35–60). Mice were tested CBD-free in adulthood (5–6 mo) in the open field task, which measures locomotion and anxiety (related to positive symptoms in schizophrenia); social interaction, which measures mouse interactions (relevant to negative symptoms); pre-pulse inhibition (PPI), which measures sensorimotor gating (deficits also found in schizophrenia patients); and fear conditioning, which measures associative learning and memory. Mice were then treated after one week washout with either 3 mg/kg of THC or vehicle, and run in a battery of open field, social interaction, and PPI tests. Brains and bloods were collected to investigate neuroinflammation after another week of washout. Western blots were used to investigate Iba1 levels, while ELISA was used to investigate levels of cytokines IL-10, IL-1B, and TNF-a.ResultsCBD treatment significantly reduced anxiety in Nrg1 TM HET mice but not WT mice, however it had no effect on locomotion in either group in the open field task. CBD treatment lowered the frequency of total social interaction in both genotypes, and reduced the frequency of social interactions of Nrg1 TM HET to WT levels. CBD reduced PPI in Nrg1 TM HET mice but not WT mice, and Nrg1 TM HET mice had lower overall PPI than WT mice. There was no effect of CBD on fear-associated memory. CBD effects on THC sensitivity in these mice are ongoing, as are brain cytokine and protein analyses.DiscussionThese results suggest that Nrg1 TM HET mice are more susceptible to the effects of chronic CBD in adolescence, despite a significant washout. This confirms previous data from our laboratory demonstrating increased susceptibility of Nrg1 TM HET male mice to cannabinoid constituents, and suggests persistent brain changes following adolescent exposure to CBD. Potential reasons for these persistent changes include an altered neuroinflammatory profile in Nrg1 TM HET mice. CBD has previously been shown to be anxiolytic in other studies and our results confirm its potential as an anxiolytic, particularly in our model of schizophrenia.

T39. IMPAIRED SENSORIMOTOR GATING USING THE ACOUSTIC PREPULSE INHIBITION PARADIGM IN INDIVIDUALS AT A CLINICAL HIGH RISK FOR PSYCHOSIS

BackgroundMany robust studies on prepulse inhibition (PPI) were conducted in patients with schizophrenia, and, increasingly, evidence has indicated individuals who are at clinical high risk for psychosis (CHR). The specificity of the PPI is insufficient with the classic paradigm. The current study investigated an improved perceived spatial separation PPI (PSSPPI) paradigm in CHR individuals, compared with patients of first-episode schizophrenia (FES) and healthy controls (HC), and the relationship between PPI, demographics, clinical characteristics, and cognitive performance.MethodsWe included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes (SIPS). The prepulse inhibition measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI paradigms were applied using 60- and 120-ms lead intervals. The MATRICS Consensus Cognitive Battery (MCCB) was used to assess neurocognitive functions.ResultsCompared with HC, the CHR group had lower PSSPPI level (ISI=60 ms, P<0.001; ISI=120 ms, P<.001). PSSPPI showed a large effect size (ES) between CHR and HC (ISI=60 ms, ES=0.91; ISI=120 ms, ES=0.98); on PSSPPI using 60-ms lead interval, ES ranged from small to large from CHR to FES. PPI deficits in CHR were unrelated to demographics, clinical characteristics, and cognition.DiscussionCHR individuals show a sensorimotor gating deficit similar to FES patients on PSSPPI of the startle response, with greater sensitivity than the classic PPI paradigm. PSSPPI appears a promising objective approach for identifying individuals at clinical high risk for psychosis related to a high risk of transition to schizophrenia.

Repeated norepinephrine receptor stimulation in the BNST induces sensorimotor gating deficits via corticotropin releasing factor

Intense stress precipitates symptoms in disorders such as post-traumatic stress (PTSD) and schizophrenia. Patients with these disorders have dysfunctional sensorimotor gating as indexed by disrupted prepulse inhibition of the startle response (PPI), which refers to decreased startle response when a weak pre-stimulus precedes a startling stimulus. Stress promotes release of norepinephrine (NE) and corticotrophin releasing factor (CRF) within the brain, neurotransmitters that also modulate PPI. We have shown that repeated stress causes sensitization of NE receptors within the basolateral amygdala (BLA) via CRF receptors and promotes long-lasting PPI disruptions and startle abnormalities. The bed nucleus of the stria terminalis (BNST) is another crucial brain region that could be involved in stress-induced alterations in NE and CRF functions to promote PPI changes as this anatomical structure is enriched in CRF and NE receptors that have been shown to regulate each other. We hypothesized that repeated infusions of NE into the BNST would cross-sensitize CRF receptors or vice versa to alter PPI. Separate groups of male Sprague Dawley rats received, CRF (200ng/0.5 μl), NE (20μg/0.5 μl), or vehicle into the BNST, once/day for 3 days and PPI was tested after each infusion. Repeated CRF-or vehicle-treated rats were then challenged with a subthreshold dose of NE (0.3μg/0.5 μl) while repeated NE-treated rats were challenged with CRF (200ng/0.5 μl), and PPI was measured. Surprisingly, initial/repeated CRF or vehicle in the BNST had no effects on PPI. In contrast, initial and repeated NE disrupted PPI. Sub-threshold NE challenge in rats that previously received repeated CRF had no effect on PPI. Interestingly though, intra-BNST challenge dose of CRF significantly disrupted PPI in rats that previously had received repeated NE infusions. Taken together, these results indicate that repeated stress-induced NE release could alter the activity of CRF receptors in the BNST to modulate sensorimotor gating as measured through PPI.

Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes

Background: Deficits in sensorimotor gating have been reported in individuals with autism spectrum disorder (ASD), as well as in ASD murine models. However, this behavior has not been examined in the neuronal subset-specific (NS)-Pten knockout (KO) model of ASD. NS-Pten KO mice exhibit hyperactivity of the PI3K/AKT/mTOR signaling pathway which is implicated in the onset of autistic deficits. This study investigates the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating. Methods: To assess sensorimotor gating in NS-Pten KO mice we utilized a three-day paradigm. On day 1 (habituation) the mice were administered 80 repetitions of a 120-dB startle stimulus. On day 2, prepulse inhibition was measured with 90 trials of the startle stimulus that was paired with a smaller (2, 7, or 12 dB) prepulse stimulus. Day 3 was assessed one week later, consisting of randomized startle trials and trials with no stimulus and was used to determine the startle response. Results: No significant difference between NS-Pten KO or wildtype (WT) mice was found for habituation (p &gt; 0.05). No significant differences were found between groups when assessing the percentage of prepulse inhibition at 2, 7, and 12 dB (p &gt; 0.05). There was also no difference in startle response between groups (p &gt; 0.05). Conclusion: Our study found that the NS-Pten KO model does not display significant deficits in sensorimotor gating processes. The present findings help to elucidate the relationship between PI3K/AKT/mTOR hyperactivation and sensory reactivity.

Studies on Haloperidol and Adjunctive α-Mangostin or Raw Garcinia mangostana Linn Pericarp on Bio-Behavioral Markers in an Immune-Inflammatory Model of Schizophrenia in Male Rats.

Schizophrenia is a severe brain disorder that is associated with neurodevelopmental insults, such as prenatal inflammation, that introduce redox-immune-inflammatory alterations and risk for psychotic symptoms later in life. Nutraceuticals may offer useful adjunctive benefits. The aim of this study was to examine the therapeutic effects of Garcinia mangostana Linn (GML) and one of its active constituents, α-mangostin (AM), alone and as adjunctive treatment with haloperidol (HAL) on schizophrenia related bio-behavioral alterations in a maternal immune-activation (MIA) model. Sprague–Dawley dams were exposed to lipopolysaccharide (LPS) (n = 18) or vehicle (n = 3) on gestational days 15 and 16. Male offspring (n = 72) were treated from PND 52–66 with either vehicle, HAL (2 mg/kg), GML (50 mg/kg), HAL + GML, AM (20 mg/kg), or HAL + AM. Control dams and control offspring were treated with vehicle. In order to cover the mood–psychosis continuum, prepulse inhibition (PPI) of startle, open field test (locomotor activity), and the forced swim test (depressive-like behavior) were assessed on PND's 64–65, followed by assay of frontal–cortical lipid peroxidation and plasma pro-inflammatory cytokines, viz. interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). MIA-induced deficits in sensorimotor gating were reversed by HAL and HAL + GML, but not GML and AM alone. MIA-induced depressive-like behavior was reversed by AM and GML alone and both in combination with HAL, with the combinations more effective than HAL. MIA-induced cortical lipid peroxidation was reversed by HAL and AM, with elevated IL-6 levels restored by GML, AM, HAL, and HAL + GML. Elevated TNF-α was only reversed by GML and HAL + GML. Concluding, prenatal LPS-induced psychotic- and depressive-like bio-behavioral alterations in offspring are variably responsive to HAL, GML, and AM, with depressive (but not psychosis-like) manifestations responding to GML, AM, and combinations with HAL. AM may be a more effective antioxidant than GML in vivo, although this does not imply an improved therapeutic response, for which trials are required.

Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4.

The human 16p11.2 gene locus is a hot-spot for copy number variations which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found the deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed the GABAergic synaptic impairment and neuronal hyper-excitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes

Background: Deficits in sensorimotor gating have been reported in individuals with autism spectrum disorder (ASD), as well as in ASD murine models. However, this behavior has not been examined in the neuronal subset-specific (NS)-Pten knockout (KO) model of ASD. NS-Pten KO mice exhibit hyperactivity of the PI3K/AKT/mTOR signaling pathway which is implicated in the onset of autistic deficits. This study investigates the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating. Methods: To assess sensorimotor gating in NS-Pten KO mice we utilized a three-day paradigm. On day 1 (habituation) the mice were administered 80 repetitions of a 120-dB startle stimulus. On day 2, prepulse inhibition was measured with 90 trials of the startle stimulus that was paired with a smaller (2, 7, or 12 dB) prepulse stimulus. Day 3 was assessed one week later, consisting of randomized startle trials and trials with no stimulus and was used to determine the startle threshold. Results: No significant difference between NS-Pten KO or wildtype (WT) mice was found for habituation (p &gt; 0.05). No significant differences were found between groups when assessing the percentage of prepulse inhibition at 2, 7, and 12 dB (p &gt; 0.05). There was also no difference in startle threshold between groups (p &gt; 0.05). Conclusion: Our study found that the NS-Pten KO model does not display significant deficits in sensorimotor gating processes. The present findings help to elucidate the relationship between PI3K/AKT/mTOR hyperactivation and sensory reactivity.

A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice.

A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia-like behaviours induced by MK-801. HCE (30, 100 or 300mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia-like animal model induced by MK-801. We conducted an acoustic startle response task, an open-field task, a novel object recognition task and a social novelty preference task. We found that a single administration of HCE (100 or 300mg/kg) ameliorated MK-801-induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK-801-induced increases in phosphorylated Akt and GSK-3β expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300mg/kg). These results imply that HCE ameliorates MK-801-induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK-3β signalling pathways.

The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer\u2019s disease in rodents

Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.

Reduced Acoustic Startle Response and Prepulse Inhibition in the Tg4-42 Model of Alzheimer's Disease.

Sensorimotor deficits have been described in several neuropsychiatric disorders including Alzheimer’s disease. The aim of the present study was to evaluate possible sensorimotor gating deficits in the Tg4-42 mouse model of Alzheimer’s disease using the prepulse inhibition task (PPI). Previous studies indicated that the hippocampus is essentially involved in the regulation of PPI. We analyzed 7-month-old homozygous Tg4-42 mice as mice at this age display severe neuron loss especially in the CA1 region of the hippocampus. Our results revealed a reduced startle response and PPI in Tg4-42 mice. The observed deficits in startle response and PPI are likely due to altered sensory processing abilities rather than hearing deficits as Tg4-42 displayed intact hearing in the fear conditioning task. The present study demonstrates for the first time that sensorimotor gating is impaired in Tg4-42 mice. Analyzing startle response as well as the PPI may offer valuable measurements to assess the efficacy of therapeutic strategies in the future in this Alzheimer’s disease model.

Neuronal subset-specific Pten-deficient mice do not exhibit deficits in sensorimotor gating processes

Background: Deficits in sensorimotor gating have been reported in individuals with autism spectrum disorder (ASD), as well as in ASD murine models. However, this behavior has been rarely examined in the neuronal subset-specific (NS)-Pten knockout (KO) model of ASD. NS-Pten KO mice exhibit hyperactivity of the PI3K/AKT/mTOR signaling pathway which is implicated in the onset of autistic deficits. This study investigates the potential relationship between PI3K/AKT/mTOR signaling and deficits in sensorimotor gating. Methods: To assess sensorimotor gating in NS-Pten KO mice we utilized a three-day paradigm. On day 1 (habituation) the mice were administered 80 repetitions of a 120-dB startle stimulus. On day 2, prepulse inhibition was measured with 90 trials of the startle stimulus that was paired with a smaller (70, 75, or 80 dB) prepulse stimulus. Day 3 was assessed one week later, consisting of randomized startle trials and trials with no stimulus and was used to determine the startle threshold. Results: No significant difference between NS-Pten KO or wildtype (WT) mice was found for habituation (p &gt; 0.05). No significant differences were found between groups when assessing the percentage of prepulse inhibition at 70, 75, and 80 dB (p &gt; 0.05). There was also no difference in startle threshold between groups (p &gt; 0.05). Conclusion: Our study found that the NS-Pten KO model does not display significant deficits in sensorimotor gating processes. The present findings help to elucidate the relationship between PI3K/AKT/mTOR hyperactivation and sensory reactivity.

Neurobehavioural complications of sleep deprivation: Shedding light on the emerging role of neuroactive steroids.

Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control. These impairments, which have profound negative consequences on the health and productivity of many individuals, reflect alterations of the prefrontal cortex (PFC) and its connectivity with subcortical regions. However, the molecular underpinnings of these alterations remain elusive. Our group and others have begun examining how the neurobehavioural outcomes of SD may be influenced by neuroactive steroids, a family of molecules deeply implicated in sleep regulation and the stress response. These studies have revealed that, similar to other stressors, acute SD leads to increased synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this up-regulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by SD, the increase in prefrontal allopregnanolone levels contributes to deficits in sensorimotor gating and impulse control, signalling a functional impairment of PFC. This scenario suggests that the synthesis of neuroactive steroids during acute SD may be enacted as a neuroprotective response in the PFC; however, such compensation may in turn set off neurobehavioural complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation.

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.

Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia.

Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology. We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model. Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated. NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC. Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.

Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Arc/Arg3.1 Deficient Mice.

Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional Arc/Arg3.1 knock-out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which Arc/Arg3.1 was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.SIGNIFICANCE STATEMENT The activity-regulated and memory-linked gene Arc/Arg3.1 has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia.

Altered synaptic scaling of PV+ interneurons underlying sensorimotor gating deficit in psychiatric disease mouse models

Altered synaptic scaling of PV+ interneurons underlying sensorimotor gating deficit in psychiatric disease mouse models

Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model.

Recent genome-wide association studies (GWAS) have identified copy number variations (CNVs) at chromosomal locus 7q36.3 that significantly contribute to the risk of schizophrenia, with all of the microduplications occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). To confirm disease causality and translate such a genetic vulnerability into mechanistic and pathophysiological insights, we have developed a series of conditional VIPR2 bacterial artificial chromosome (BAC) transgenic mouse models of VIPR2 CNV. VIPR2 CNV mouse model recapitulates gene expression and signaling deficits seen in human CNV carriers. VIPR2 microduplication in mice elicits prominent dorsal striatal dopamine dysfunction, cognitive, sensorimotor gating, and social behavioral deficits preceded by an increase of striatal cAMP/PKA signaling and the disrupted early postnatal striatal development. Genetic removal of VIPR2 transgene expression via crossing with Drd1a-Cre BAC transgenic mice rescued the dopamine D2 receptor abnormality and multiple behavioral deficits, implicating a pathogenic role of VIPR2 overexpression in dopaminoceptive neurons. Thus, our results provide further evidence to support the GWAS studies that the dosage sensitivity intolerance of VIPR2 is disease causative to manifest schizophrenia-like dopamine, cognitive, and social behavioral deficits in mice. The conditional BAC transgenesis offers a novel strategy to model CNVs with a gain-of -copies and facilitate the genetic dissection of when/where/how the genetic vulnerabilities affect development, structure, and function of neural circuits. Our findings have important implications for therapeutic development, and the etiology-relevant mouse model provides a useful preclinical platform for drug discovery.

Neurochemical evidence that cysteamine modulates amphetamine-induced dopaminergic neuronal activity in striatum by decreasing dopamine release: an in vivo microdialysis study in freely moving rats

Elevated striatal dopamine release is thought to be one of the hallmarks of schizophrenia and correlates with its positive symptoms. Cysteamine (2-aminoethane-1-thiol), a compound naturally found in mammalian cells, inhibits amphetamine-induced dopamine-mediated increases in locomotor activity and behavior and blocks amphetamine-induced deficits in sensorimotor gating, suggesting cysteamine interaction with the dopaminergic system. Therefore, in the present study, we examined, in vivo, in the striatum of awake, freely moving rats the effect of cysteamine on the basal and amphetamine-induced release of dopamine, given also the fact that amphetamine-induced psychosis is a widely accepted animal model of schizophrenia. In vivo transversal microdialysis was used to collect the striatal dialysate samples and high performance liquid chromatography (HPLC), coupled with electrochemical detection- to assess the samples dopamine levels. Amphetamine,1μM, administered locally through the microdialysis fiber, running through both the left and right striatum, produced a significant increase in the extracellular level of dopamine. The increase lasted over an hour when dopamine gradually returned to its basal levels. Cysteamine hydrochloride, perfused locally in the sriatum via the microdialysis probe, at a concentration of 100 μM did not change the basal release of dopamine. However, at the same concentration and administered together with amphetamine, 1μM, it completely inhibited the stimulant effect of amphetamine.To our knowledge, our in vivo results are the first to show direct neurochemical evidence that cysteamine is able to modulate amphetamine-induced dopamine neuronal activity in the striatum of awake, freely moving rats by suppressing the increased by amphetamine release of dopamine.