A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse.
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ABSTRACT:
SUBMITTER: Jeans AF
PROVIDER: S-EPMC1793901 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We characterized the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which model the hemi-deletion we found in human subjects with schizophrenia, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity compared to wildtype (WT) mice. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood of the HET mice compared to WT mice.
2017-08-29 | GSE103194 | GEO
Project description:BackgroundHIV-associated neurocognitive disorder (HAND) is commonly observed in persons living with HIV (PWH) and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in animals.MethodsPPI was measured in male and female HIVtg rats and wild-type controls following acute, nonconcurrent treatment with the primary constituents of cannabis: Δ 9-tetrahydrocannabinol (THC; 1 and 3 mg/kg, s.c.) and cannabidiol (1, 10, and 30 mg/kg, i.p.).ResultsHIVtg rats exhibited a significant PPI deficit relative to wild-type controls. THC reduced PPI in controls but not HIVtg rats. Cannabidiol exerted only minor, genotype-independent effects on PPI.ConclusionsHIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use among PWH.
| S-EPMC8598295 | biostudies-literature
Project description:Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.
| S-EPMC2720138 | biostudies-literature
Project description:The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.
| S-EPMC4531139 | biostudies-literature
Project description:Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen's d = 0.91; ISI = 120 ms, Cohen's d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.
| S-EPMC7825103 | biostudies-literature
Project description:We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.
| S-EPMC5590851 | biostudies-literature
Project description:Glutamate dysregulation is known to contribute to many psychiatric disorders including schizophrenia. Aberrant cortico-striatal activity and therefore glutamate levels might be relevant to this disease characterized by reduced prepulse inhibition (PPI), however, the molecular and behavioral mechanism of the pathophysiology of schizophrenia remains unclear. The focus of this study was to contribute to the current understanding of the glutamate and neurogranin (Ng) pathway, in relation to the cortico-striatal pathology of schizophrenia using a mouse model. A variant of the Ng gene has been detected in people with schizophrenia, implicating maladaptation of cortical glutamate signaling and sensorimotor gating. To test Ng-mediated PPI regulation in the mouse model, we utilized Ng null mice, viral-mediated Ng expression, and genetics approaches. Our results demonstrate that lack of Ng in mice decreases PPI. Ng over-expression in the prefrontal cortex (PFC) increases PPI, while Ng expression in either the nucleus accumbens (NAc) or hippocampus induces no change in PPI. Using optogenetics and chemogenetics, we identified that cortico-striatal activation is involved in PPI regulation. Finally, pharmacological regulation of Ng using glutamate receptor inhibitors demonstrated altered PPI between genotypes. In this study, we have investigated the impact of Ng expression on sensorimotor gating. This study contributes to a better understanding of the glutamatergic theory of schizophrenia, opening novel therapeutic avenues that may lead to glutamatergic treatments to ameliorate the symptoms of schizophrenia.
| S-EPMC6475612 | biostudies-literature
Project description:Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.
| S-EPMC4548234 | biostudies-literature
Project description:BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.
| S-EPMC8056086 | biostudies-literature
Project description:BackgroundWe investigated whether balance impairments caused by cerebellar disease are associated with specific sensorimotor processing deficits that generalize across all sensory modalities. Experiments focused on the putative cerebellar functions of scaling and coordinate transformation of balance responses evoked by stimulation of single sensory channels.MethodsVestibular, visual, and proprioceptive sensory channels were stimulated in isolation using galvanic vestibular stimulation, moving visual scenery, and muscle vibration, respectively, in 16 subjects with spinocerebellar ataxia type 6 (SCA6) and 16 matched healthy controls. Two polarities of each stimulus type evoked postural responses of similar form in the forward and backward directions. Disease severity was assessed using the Scale for Assessment and Rating of Ataxia.ResultsImpaired balance of SCA6 subjects during unperturbed stance was reflected in faster than normal body sway (P = 0.009), which correlated with disease severity (r = 0.705, P < 0.001). Sensory perturbations revealed a sensorimotor processing abnormality that was specific to response scaling for the visual channel. This manifested as visually evoked postural responses that were approximately three times larger than normal (backward, P < 0.001; forward P = 0.005) and correlated with disease severity (r = 0.543, P = 0.03). Response direction and habituation properties were no different from controls for all three sensory modalities.ConclusionCerebellar degeneration disturbs the scaling of postural responses evoked by visual motion, possibly through disinhibition of extracerebellar visuomotor centers. The excessively high gain of the visuomotor channel without compensatory decreases in gains of other sensorimotor channels provides a potential mechanism for instability of the balance control system in cerebellar disease.
| S-EPMC4949507 | biostudies-literature