Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Reduced phosphorylation of synapsin I in the hippocampus of Engrailed-2 knockout mice, a model for autism spectrum disorders.

Mice lacking the homeodomain transcription factor Engrailed-2 (En2(-/-) mice) are a well-characterized model for autism spectrum disorders (ASD). En2(-/-) mice present molecular, neuropathological and behavioral deficits related to ASD, including down-regulation of ASD-associated genes, cerebellar hypoplasia, interneuron loss, enhanced seizure susceptibility, decreased sociability and impaired cognition. Specifically, impaired spatial learning in the Morris water maze (MWM) is associated with reduced expression of neurofibromin and increased phosphorylation of extracellular-regulated kinase (ERK) in the hippocampus of En2(-/-) adult mice. In the attempt to better understand the molecular cascades underlying neurofibromin-dependent cognitive deficits in En2 mutant mice, we investigated the expression and phosphorylation of synapsin I (SynI; a major target of neurofibromin-dependent signaling) in the hippocampus of wild-type (WT) and En2(-/-) mice before and after MWM. Here we show that SynI mRNA and protein levels are down-regulated in the hippocampus of naïve and MWM-treated En2(-/-) mice, as compared to WT controls. This down-regulation is paralleled by reduced levels of SynI phosphorylation at Ser549 and Ser553 residues in the hilus of mutant mice, before and after MWM. These data indicate that in En2(-/-) hippocampus, neurofibromin-dependent pathways converging on SynI phosphorylation might underlie hippocampal-dependent learning deficits observed in En2(-/-) mice.

DJ-1 is a Parkinson's disease susceptibility gene in southern Italy.

Mutations in the gene DJ-1 have been shown to be a rare cause of early-onset Parkinson's disease (EOPD). Since DJ-1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ-1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single-nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36-3.08). When we considered a three-marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ-1 gene confer risk to sporadic PD in southern Italy.

Alpha-synuclein promoter haplotypes and dementia in Parkinson's disease.

Dementia is a common complication of Parkinson's disease (PD). It correlates significantly with the presence of cortical, limbic or nigral Lewy bodies, mainly constituted of alpha-synuclein. Mutations of the alpha-synuclein gene (SNCA) have been linked to rare familial forms of PD, while association studies on the promoter polymorphisms have given conflicting results in sporadic patients. We have performed a case control study to investigate whether genetic variability in the promoter of the alpha-synuclein gene could predispose to dementia in PD. A total of 114 demented patients and 114 non-demented patients with sporadic PD were included in the study. Six polymorphic loci (including the Rep1 microsatellite) in the promoter of the SNCA gene were examined. Each marker, taken individually, did not show association to dementia and no significant differences were observed in the inferred haplotype frequencies of demented and non-demented patients. Our data suggest the lack of involvement of the SNCA promoter in the pathogenesis of dementia in PD. Further studies in other populations are needed to confirm these results.

Perinatal exposure to 5-methoxytryptamine, behavioural-stress reactivity and functional response of 5-HT1A receptors in the adolescent rat.

Serotonin is involved in a wide range of physiological and patho-physiological mechanisms. In particular, 5-HT1A receptors are proposed to mediate stress-adaptation. The aim of this research was to investigate in adolescent rats: first, the consequences of perinatal exposure to 5-metoxytryptamine (5MT), a 5-HT1/5-HT2 serotonergic agonist, on behavioural-stress reactivity in elevated plus maze, open field and forced swim tests; secondly, whether the behavioural effects induced by perinatal exposure to 5MT on open field and forced swim tests were affected by the selective 5-HT1A receptor agonist LY 228729, a compound able to elicit a characteristic set of motor behaviours on these experimental models, and by the co-administration of the selective and silent 5-HT1A antagonist WAY 100635. Results indicate that a single daily injection of 5MT to, pregnant dams from gestational days 12 to 21 (1mg/kg s.c.), and to the pups from postnatal days 2 to 18 (0.5mg kg s.c.), induce in the adolescent rat offspring: an increase in the percentage of entries and time spent on the open arms in the elevated plus maze; a reduction in locomotor activity and rearing frequency, and an increase in the time spent on the central areas in the open field test; a decrease in immobility and an increase in swimming in the forced swim test. Acute administration of LY 228729 (1.5mg/kg s.c.) strongly decreases rearing frequency and increases peripheral activity in the open field test, and decreases immobility and increases swimming in the forced swim test both in perinatally vehicle and 5MT-exposed offspring. Co-administration of WAY 100635 (0.25mg/kg s.c.) abolishes the effects exerted by LY 228729. These results suggest that, in the adolescent rat, perinatal exposure to 5MT enhances the stress-related adaptive behavioural responses, presumably through a predominant action on presynaptic 5-HT1A receptors and does not deteriorate the functional response of 5-HT1A receptors to selective agonist and antagonist compounds.

Disseminação do vírus da doença de Aujeszky, envolvendo o comércio de reprodutores suínos de reposição / Spread of virus of Aujeszky's disease by the trade of replacement swine breeders

Relata-se a disseminação da infeção pelo vírus da doença de Aujeszky (VDA) a partir da comercialização de reprodutores suínos oriundos de duas granjas de reprodutores suídeos certificada (GRSC) que tiveram surto da DA. Após a confirmação do diagnóstico de DA, os suínos comercializados 37 a 45 dias anteriores aos surtos foram recolhidos, submetidos ao exame sorológico para o VDA e enviados ao abate. Nos rebanhos-destino foram realizados exames sorológicos para o VDA 17 a 37 dias após o recolhimento, naqueles que estavam lojados nas baias vizinhas àquelas onde haviam sido alojados os suínos comprados; seis meses mais tarde, foi realizada outra sorologia por amostragem dos reprodutores. No total, 52 rebanhos compraram suínos das duas granjas, e, destes, 37 (69,8 por cento) receberam, pelo menos, um animal com sorologia positiva para o VDA. Somente sete (18,9 por cento) deles apresentaram sorologia positiva para o VDA, e em 30 (81,1 por cento), não houve indícios de disseminação da infecção. A contaminação pelo VDA de granjas GRSC representa enorme potencial para a disseminação da infecção, por meio do comércio de suínos de reposição. A rastreabilidade dos animais comercializados em um período anterior ao diagnóstico, com imediata remoção dos lotes de suínos dos rebanhos-destino, evitou a disseminação da infecção

It was reported the spreading of the infection caused by the virus of Aujesky's disease (VAD) by the commercialization of breeders originated from two pigs farms GRSC (Farms of Certified Swine Breeders - FCSB) which had an outbreak of Aujeszky's disease. After the positive diagnosis of Aujesky's disease, the pigs traded from 37 to 45 day before the outbreaks were removed from the herd, bled for serological exams for the VAD and sent to slaughterhouses. The herds which received these pigs were serologically tested for the VAD, 17 to 37 days after the removal of the animals. Serological tests were also performed in pigs lodged at neighboring cages to those which had been lodged with the pigs bought and a sampling test was done six months later. Thus, 52 flocks bought pigs from the farms 1 and 2. From those, 37 (69.8 percent) received at least one serum-positive pig for the VAD. Only seven (18.9 percent) of them were infected and 30 (81.1 percent) pigs showed no indications of infection by the VAD. The occurrence of VAD in FCSB farms represents huge potential for spreading of the VAD, by the trade of replacement pigs. The traceability investigation and removal of the animals traded before the diagnosis, with immediate removal of the positive lots of pigs at the destiny herd, avoided the spread of the infection

Effects of 8-OH-DPAT on open field performance of young and aged rats prenatally exposed to diazepam: a tool to reveal 5-HT1A receptor function.

Central GABAergic and serotoninergic systems interact with one another and are implicated in controlling different behaviours. A gentle early long-lasting handling can prevent the deficits in locomotion and exploration in open field (O.F.) in 3-month-old male rats prenatally exposed to diazepam (DZ). Purpose of this study was to extend the research to older handled rats prenatally exposed to DZ and to assess the activity of 5-HT1A receptors (Rs), evaluating the performance in O.F. at 3 and 18 months of age following 8-OH-DPAT administration. A single daily s.c. injection of DZ (1.5 mg/kg) from gestation day 14 to gestation day 20 induced in aged, but not in young rats, a decrease in total distance travelled (TDT) and in rearing frequency (RF) and an increase of transitions from the periphery to the centre of the arena (CNT) and in the time spent in the centre of the arena (CAT), compared to controls. 8-OH-DPAT (0.150 mg/kg s.c.), given 1 h before testing, increased TDT and decreased RF, CNT and CAT in both vehicle- and DZ-exposed young rats. In aged rats prenatally exposed to DZ, 8-OH-DPAT induced an increase in TDT and a slight decrease in RF, CNT and CAT. These findings indicate that the effects of handling and of 8-OH-DPAT in prenatally DZ-exposed rats are age-dependent and suggest that O.F. test can represent a valid tool to identify the changes in 5-HT1A Rs activity following drug treatment.