BackgroundAutism spectrum disorder (ASD) is characterized by impaired social interactions and repetitive patterns of behavior. Symptoms appear in early life and persist throughout adulthood. Early social stimulation can help reverse some of the symptoms, but the biological mechanisms of these therapies are unknown. By analyzing the effects of early social stimulation on ASD-related behavior in the mouse, we aimed to identify brain structures that contribute to these behaviors.MethodsWe injected pregnant mice with 600-mg/kg valproic acid (VPA) or saline (SAL) at gestational day 12.5 and evaluated the effect of weaning their offspring in cages containing only VPA animals, only SAL animals, or mixed. We analyzed juvenile play at PD21 and performed a battery of behavioral tests in adulthood. We then used preclinical PET imaging for an unbiased analysis of the whole brain of these mice and studied the function of the piriform cortex by c-Fos immunoreactivity and HPLC.ResultsCompared to control animals, VPA-exposed animals play less as juveniles and exhibit a lower frequency of social interaction in adulthood when reared with other VPA mice. In addition, these animals were less likely to investigate social odors in the habituation/dishabituation olfactory test. However, when VPA animals were weaned with control animals, these behavioral alterations were not observed. Interestingly, repetitive behaviors and depression-related behaviors were not affected by social enrichment. We also found that VPA animals present high levels of glucose metabolism bilaterally in the piriform cortex (Pir), a region known to be involved in social behaviors. Moreover, we found alterations in the somatosensory, motor, and insular cortices. Remarkably, these effects were mostly reversed after social stimulation. To evaluate if changes in glucose metabolism in the Pir correlated with changes in neuronal activity, we measured c-Fos immunoreactivity in the Pir and found it increased in animals prenatally exposed to VPA. We further found increased dopamine turnover in the Pir. Both alterations were largely reversed by social enrichment.ConclusionsWe show that early social enrichment can specifically rescue social deficits in a mouse model of ASD. Our results identified the Pir as a structure affected by VPA-exposure and social enrichment, suggesting that it could be a key component of the social brain circuitry.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0221-9) contains supplementary material, which is available to authorized users.

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein Tau, which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in tau pre-mRNA produces equal amounts of protein isoforms with either three (3 R) or four (4 R) microtubule binding domains. Imbalance in the 3 R : 4 R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as Progressive Supranuclear Palsy and Corticobasal Degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which bear abnormal 3 R : 4 R tau isoforms contents, and contrariwise to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses pointed the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results constitute readout that abnormal striatal tau-isoforms contents might lead to parkinsonian-like phenotypes and provide proof of concept that modulation of tau mis-splicing could be a plausible disease-modifying therapy for some primary tauopathies.

Background: Schizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood. The etiology of this disease remains unknown. An objective diagnostic approach is required. Here, we used a mouse model that shows schizophrenia-like phenotypes to study brain glucose metabolism and presynaptic dopaminergic functioning by positron emission tomography (PET) and immunohistochemistry. PET scannings were performed on mice after the administration of [ 18 F]-FDG or [ 18 F]-F-DOPA. Glucose metabolism was evaluated in basal conditions and after the induction of a hyperdopaminergic state. Results: Mutant animals show reduced glucose metabolism in prefrontal cortex, amygdala, and nucleus reuniens under the hyperdopaminergic state. They also show reduced [ 18 F]-F-DOPA uptake in prefrontal cortex, substantia nigra reticulata, raphe nucleus, and ventral striatum but increased [ 18 F]-F-DOPA uptake in dorsal striatum. Mutant animals also show reduced tyrosine hydroxylase expression on midbrain neurons. Conclusions: Dopamine D2 mutant animals show reduced glucose metabolism and impaired presynaptic dopaminergic functioning, in line with reports from human studies. This mouse line may be a valuable model of schizophrenia, useful to test novel tracers for PET scanning diagnostic.

Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long‐distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post‐natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon–oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.

Objective: To determine whether technetium-99m-labeled tropane derivative single-photon emission computed tomography (99mTc-TRODAT-1 SPECT) provides results comparable to those of the less widely available, less accessible tool fluorine-18-labeled fluorodopa positron-emission tomography (18F-FDOPA PET) in the setting of a movement disorders clinic. Materials and Methods: In this prospective pilot study, eight subjects with a clinical diagnosis of Parkinson’s disease were randomly selected from among patients under treatment at a movement disorders clinic and submitted to 99mTc-TRODAT-1 SPECT and 18F-FDOPA PET. The results were read by two experienced observers, and a semiquantitative analysis was performed. Results: The visual and semiquantitative analyses were concordant for all studies, showing that radiotracer uptake in the contralateral striatum on the most affected side was lower when 99mTc-TRODAT-1 SPECT was employed. The semiquantitative analysis demonstrated a significant correlation between 18F-FDOPA PET and 99mTc-TRODAT-1 SPECT (r = 0.73; p < 0.01). Conclusion: It appears that 99mTc-TRODAT-1 SPECT is a valid option for the study of dopaminergic function in a clinical setting.