Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

Genetic Variation in the Vesicular Monoamine Transporter 1 (VMAT1/SLC18A1) Gene and Alcohol Withdrawal Severity.

BACKGROUND: Alcohol withdrawal (AW) can be a serious consequence of alcohol dependence and consists of various neurochemical adaptations in the brain. One such neuroadaptation occurs in the monoamine neurotransmitter system. Recently, a functional variant in the presynaptic vesicular monoamine transporter gene (VMAT1/SLC18A1-Thr136Ile-rs1390938) was found to significantly increase transport of monoamines into synaptic vesicles in vitro. We hypothesize that the alteration of magnitude of monoamine release contributes to severity of AW symptoms. METHODS: Alcohol-dependent individuals (n = 609; European American n = 340; African American n = 216; other n = 53) were administered the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) questionnaire at the time of inpatient admission. Patients were subsequently genotyped for 12 single nucleotide polymorphism (SNP) markers in VMAT1. Association analyses were conducted on the combined sample and separated by ethnicity. RESULTS: Single marker association tests revealed a significant association between 3 VMAT1 markers and CIWA-Ar scores in the EA sample. The minor alleles of rs1390938 (A) and rs952859 (C) were significantly associated with lower CIWA-Ar scores (p = 0.0006; p = 0.0007), whereas the minor allele of rs3779672 (G) was significantly associated with higher scores (p = 0.006). Additionally, these 3 SNPs were found in a haplotype block that was significantly associated with lower CIWA-Ar scores after haplotype analyses were run (p = 0.009). CONCLUSIONS: This study shows that genetic variants in VMAT1, including the functional SNP rs1390938, contribute to the severity of AW in patients of European descent. Our data show for the first time a role of presynaptic neurotransmitter release in AW severity. This finding could contribute to identifying patients at risk for severe AW and shed light into the pathophysiology of AW and its treatment.

Resting-state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence.

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

Mechanism of action of celecoxib on normal and acid-challenged gastric mucosa.

Selective COX-2 inhibitor, celecoxib, delays the healing of gastric ulcers by inhibiting prostaglandins synthesis. Therefore, the effect of celecoxib on normal and acid-challenged gastric mucosa was studied. Wistar rats were distributed into four groups: group-1 (vehicle treated), group-2 (celecoxib treated), group-3 (given 0.6N HCl) and group-4 (HCl+celecoxib treated). The gastric mucosa was assessed histopathologically and by evaluating gastric adherent mucus. To assess the role of oxidative stress, the levels of free radicals and antioxidants were measured. The histopathological examination showed mild inflammation in group-2, moderate inflammation in group-3 and severe inflammation in group-4. The results showed an increase in malondialdehyde and a decrease in gastric adherent mucus, nitrite, reactive thiols and glutathione in groups-2-4 as compared to control group. Activity of superoxide dismutase, catalase and glutathione-s-transferase was increased in all the groups except the group-1. The present study suggested that celecoxib aggravated the gastric damage caused by acid which may be mediated by altering the balance between free radicals and antioxidants.

Role of oxidative stress in celecoxib-induced renal damage in wistar rats.

Celecoxib, a selective cyclo-oxygenase-2 (Cox-2) inhibitor, prevents the formation of prostaglandins, responsible for maintenance of renal function. Celecoxib administration may lead to renal damage. Since free radicals and antioxidant mechanisms play a significant role in renal injury; this study was designed to evaluate the role of oxidative stress in celecoxib-induced renal damage. The administration of celecoxib resulted in moderate and mild tubulointerstitial nephritis in chronic and acute group. The renal function tests were significantly altered only in the chronic group. The results in both the acute and the chronic group showed (1) a significant increase in the lipid peroxidation and in the activities of superoxide dismutase, catalase and glutathione-S-transferase and (2) a decrease in nitrite, reactive thiols and glutathione. In conclusion, our study suggests that chronic administration of celecoxib may have a damaging effect on kidney, as evident through altered histopathology and renal functions. This damage may be mediated by oxidative stress.