Valproic Acid Rats Research Articles

Abnormal spatiotemporal expression pattern of progranulin and neurodevelopment impairment in VPA-induced ASD rat model

Some environmental risk factors have been proven to contribute to the etiology of autism spectrum disorder (ASD). Exposure to the antiepileptic drug valproic acid (VPA) during pregnancy significantly increases the risk of ASD in humans, and consequently is utilized as a validated animal model of ASD in rodents; however, the precise molecular and cellular mechanisms remain ill-defined. In the present study, we investigated the effect of prenatal VPA exposure on the spatiotemporal dynamics of Progranulin (PGRN) expression, neuronal apoptosis, synapse density, and AKT/GSK-3β pathway activation in the brains of VPA-exposed offspring. Results from behavioral tests were consistent with prior studies showing impaired sociability, restricted interests and increased repetitive behaviors in VPA rats at postnatal days 28–32. Our data also indicated that VPA exposure resulted in abnormal dynamics of PGRN expression in different brain regions at the different development stages. The temporal and spatial patterns of PGRN expression were consistent with the spatiotemporal regularity of abnormalities, which observed in apoptosis-related protein levels, neuron numbers, dendritic spine density, synapse-related protein levels, and AKT/GSK-3β phosphorylation in VPA rats. It suggests that prenatal VPA exposure may affect the spatiotemporal regularity of neuronal apoptosis and synaptic development/regression via interfering with the spatiotemporal process of PGRN expression and downstream AKT/GSK-3β pathway activation. This may be a potential mechanism of the abnormal neuroanatomical changes and ASD-like behaviors in VPA-induced ASD.

Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder.

Recently it has been proposed that impairments related to autism spectrum disorder (ASD) may reflect a more fundamental disruption in time perception. Here, we examined whether in utero exposure to valproic acid (VPA) can generate specific behavioral deficits related to ASD and time perception. Pups from control and VPA groups were tested using fixed-interval (FI) temporal bisection, peak interval, and intertemporal choice tasks. In addition, the rats were assessed on motor function, perseverative and exploratory behavior, anxiety, and memory. The VPA group displayed a leftward shift in timing functions. VPA rats displayed no deficits on the motor and memory tasks, but were significantly different from controls on measures of perseveration and anxiety.

Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders

BackgroundAutism spectrum disorders (ASD) are synaptopathies characterized by area-specific synaptic alterations and neuroinflammation. Structural and adhesive features of hippocampal synapses have been described in the valproic acid (VPA) model. However, neuronal and microglial contribution to hippocampal synaptic pattern and its time-course of appearance is still unknown.MethodsMale pups born from pregnant rats injected at embryonic day 10.5 with VPA (450 mg/kg, i.p.) or saline (control) were used. Maturation, exploratory activity and social interaction were assessed as autistic-like traits. Synaptic, cell adhesion and microglial markers were evaluated in the CA3 hippocampal region at postnatal day (PND) 3 and 35. Primary cultures of hippocampal neurons from control and VPA animals were used to study synaptic features and glutamate-induced structural remodeling. Basal and stimuli-mediated reactivity was assessed on microglia primary cultures isolated from control and VPA animals.ResultsAt PND3, before VPA behavioral deficits were evident, synaptophysin immunoreactivity and the balance between the neuronal cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) were preserved in the hippocampus of VPA animals along with the absence of microgliosis. At PND35, concomitantly with the establishment of behavioral deficits, the hippocampus of VPA rats showed fewer excitatory synapses and increased NCAM/PSA-NCAM balance without microgliosis. Hippocampal neurons from VPA animals in culture exhibited a preserved synaptic puncta number at the beginning of the synaptogenic period in vitro but showed fewer excitatory synapses as well as increased NCAM/PSA-NCAM balance and resistance to glutamate-induced structural synaptic remodeling after active synaptogenesis. Microglial cells isolated from VPA animals and cultured in the absence of neurons showed similar basal and stimuli-induced reactivity to the control group. Results indicate that in the absence of glia, hippocampal neurons from VPA animals mirrored the in vivo synaptic pattern and suggest that while neurons are primed during the prenatal period, hippocampal microglia are not intrinsically altered.ConclusionsOur study suggests microglial role is not determinant for developing neuronal alterations or counteracting neuronal outcome in the hippocampus and highlights the crucial role of hippocampal neurons and structural plasticity in the establishment of the synaptic alterations in the VPA rat model.

Brain and plasma amino acid concentration in infant rats prenatally exposed to valproic acid.

Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.

Valproic acid treated female Long-Evans rats are impaired on attentional set-shifting

Autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by social deficits, communication impairments, restrictive behaviors, and cognitive flexibility deficits. The valproic acid (VPA) model of autism has been widely used to examine changes in rodent behavior and neurobiology to better understand ASD. This study examined social and anxiety behavior as well as cognitive flexibility in VPA and control offspring. Results for social behavior were consistent with prior studies showing reduced sociability in VPA rats and increased self-grooming, which may be viewed as a repetitive behavior. VPA rats also had deficits in performing the set-shifting task, with female VPA rats demonstrating greater impairment compared to female control rats and male VPA rats. These results support the hypothesis that females diagnosed with ASD may suffer from different symptoms and present a unique behavioral profile compared to males with ASD. Female VPA rats were also less likely to form an attentional set; offering evidence that the VPA model of autism is encompassing executive function deficits similar to those observed in humans with ASD.

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats.

Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function, repetitive and restricted behaviors. Valproic acid (VPA) was reported to increase the prevalence of ASD in humans as a consequence of its use during pregnancy. VPA treatment also induces autistic-like behaviors in the offspring of rats after prenatal exposure; hence it is a preclinical disease model with high translational value. In the present study, our aim was to characterize ASD relevant behaviors of socially housed, individually identified male rats in automated home cages. The natural behavior of rats was assessed by monitoring their visits to drinking bottles in an environment without human influence aiming at reducing interventional stress. Although rodents normally tend to explore their new environment, prenatally VPA-treated rats showed a drastic impairment in initial and long-term exploratory behavior throughout their stay in the automated cage. Furthermore, VPA rats displayed psychogenic polydipsia (PPD) as well as altered circadian activity. In the competitive situation of strict water deprivation controls switched to an uneven resource sharing and only a few dominant animals had access to water. In VPA animals similar hierarchy-related changes were completely absent. While the control rats secured their chance to drink with frequent reentering visits, thereby “guarding” the water resource, VPA animals did not switch to uneven sharing and displayed no evidence of guarding behavior.

Effects of single-dose antipurinergic therapy on behavioral and molecular alterations in the valproic acid-induced animal model of autism

Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic signaling system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a non-selective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20 mg/kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment did not affect VPA-induced upregulation of P2X4 and P2Y2 receptor expression in the hippocampus, and P2X4 receptor expression in the medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic signaling modulation in behavioral, molecular, and immunological aberrations described in VPA model, and indicate that the purinergic signaling system might be a potential target for pharmacotherapy in preclinical studies of ASD.

Increased Expression of Kv10.2 in the Hippocampus Attenuates Valproic Acid-Induced Autism-Like Behaviors in Rats.

The role of potassium channels provides suggestive evidence for the etiology of autism. The voltage-gated potassium channel Kv10.2 (KCNH5) is widely expressed in the brain. However, the inherent relationship between Kv10.2 and autism is still unclear. Herein, a rat valproic acid (VPA)-induced autism spectrum disorder model was established. The expression level of Kv10.2 was obviously decreased in the hippocampus of VPA rats. Kv10.2 was mainly localized in neurons. Subsequently, a recombinant lentivirus expressing Kv10.2 was used to upregulate the expression of Kv10.2 in the hippocampus of VPA-exposed rats. The results were promising as injection of the Kv10.2 lentivirus in the hippocampus relieved anxiety and stereotypical behavior, and improved the social and exploratory abilities of rats that were prenatally exposed to VPA. In addition, spectral analysis of electroencephalogram data revealed that animals exposed to VPA exhibited increased high-frequency activity compared with the control rats, and this activity recovered to a certain extent after upregulation of Kv10.2 expression by lentivirus injection. These results suggest that changes in Kv10.2 may play an important role in the etiology of autism, thus providing a promising direction for further research on autism.

The Notch signaling pathway inhibitor Dapt alleviates autism-like behavior, autophagy and dendritic spine density abnormalities in a valproic acid-induced animal model of autism

Autism spectrum disorders (ASDs) comprise a number of heterogeneous neurodevelopmental diseases. Recent studies suggest that the abnormal transmission of neural signaling pathways is associated with the pathogenesis of autism. The aim of this study was to identify a link between the Notch signaling pathway and the pathogenesis of autism. In this study, we demonstrated that prenatal exposure to valproic acid (VPA) resulted in autistic-like behaviors in offspring rats and that the expression of the Notch signaling pathway-related molecules Notch1, Jagged1, Notch intracellular domain (NICD) and Hes1 increased in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA rats compared to those of controls. However, inhibiting the Notch pathway with (3,5-Difluorophenacetyl)-L-alanyl-S-phenylglycine-2-butyl Ester (Dapt) reduced the overexpression of Notch pathway-related molecules in offspring rats. Notably, Dapt improved autistic-like behaviors in a VPA-exposed rat model of autism. Furthermore, we investigated whether Dapt improved autistic-like behavior in a VPA rat model by regulating autophagy and affecting the morphology of dendritic spines. We found that the expression of the autophagy-related proteins Beclin 1, LC3B and phospho-p62 in the PFC, HC and CB of VPA model rats increased after Notch signal activation and was inhibited by Dapt compared to those of controls. Moreover, postsynaptic density-95 (PSD-95) protein expression also increased significantly compared to that of VPA model rats. The density of dendritic spines decreased in the PFC of VPA rats treated with Dapt compared to that of VPA model rats. Our present results suggest that VPA induces an abnormal activation of the Notch signaling pathway. The inhibition of excessive Notch signaling activation by Dapt can alleviate autistic-like behaviors in VPA rats. Our working model suggests that the Notch signaling pathway participates in the pathogenesis of autism by regulating autophagy and affecting dendritic spine growth. The results of this study may help to elucidate the mechanism underlying autism and provide a potential strategy for treating autism.

Valproic acid changes the expression of tyrosine-phosphorylated proteins in rat seminal vesicle.

Previous studies reported the effects of valproic acid (VPA) on tyrosine-phosphorylated (TyrPho) protein expression in the testis and epididymis, but its effects on that in the seminal vesicle (SV) have never been demonstrated. This study attempted to investigate the expressions of TyrPho proteins in SV treated with VPA. Sixteen rats were divided into control and VPA-treated groups. The control rats were injected with normal saline, whereas the treated animals were intraperitoneally injected with VPA (500mg/kg BW) for 10 consecutive days (n=8/each). The biochemical parameters in blood plasma and SV fluid were analysed. The SV tissues and fluid were investigated for the presence and expression of TyrPho proteins, androgen receptor (AR) proteins and heat shock protein 70 (Hsp70). Significantly, VPA caused SV atrophy and reductions in secretion and biochemical parameter levels. There were significant increases in many TyrPho proteins in the plasma (a 95kDa) and SV tissue (a 40kDa) of the VPA rats. However, the expressions of seminal AR, Hsp70 and TyrPho proteins (50 and 48kDa) were significantly lower in VPA rats. Recent results have indicated that VPA affected SV morphology and decreased biochemical fluid substances including TyrPho proteins associated with decreased expressions of AR and Hsp70.

Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism.

Autism spectrum disorder (ASD) is characterized by impaired social communication and repetitive/stereotyped behaviors. The neuropeptide oxytocin (OXT) plays a critical role in regulating social behaviors in the central nervous system, as indicated in both human and animal studies. We hypothesized that central OXT deficit is one of causes of etiology of ASD, which may be responsible for the social impairments. To test our hypothesis, central OXT system was examined in valproic acid (VPA)-induced rat model of autism (VPA rat). Our results showed that adolescent VPA rats exhibited a lower level of OXT mRNA and fewer OXT-ir cells in the hypothalamus than control rats. Additionally, OXT concentration in cerebrospinal fluid (CSF) was reduced. The number of OXT-ir cells in the supraoptic nucleus (SON) of neonatal VPA rats was also lower. Autistic-like behaviors were observed in these animals as well. We found that an acute intranasal administration of exogenous OXT restored the social preference of adolescent VPA rats. Additionally, early postnatal OXT treatment had long-term effects ameliorating the social impairments and repetitive behaviors of VPA rats until adolescence. This was accompanied by an increase in OXT-ir cells. Taken together, we demonstrated there was central OXT deficiency in the VPA-induced rat model of autism, and showed evidence that early postnatal OXT treatment had a long-term therapeutic effect on the autistic-like behaviors in VPA rats.

A Developmental Study of Abnormal Behaviors and Altered GABAergic Signaling in the VPA-Treated Rat Model of Autism.

Although studies have investigated the role of gamma-aminobutyric acid (GABA)ergic signaling in rodent neural development and behaviors relevant to autism, behavioral ontogeny, as underlain by the changes in GABAergic system, is poorly characterized in different brain regions. Here, we employed a valproic acid (VPA) rat model of autism to investigate the autism-like behaviors and GABAergic glutamic acid decarboxylase 67 (GAD67) expression underlying these altered behaviors in multiple brain areas at different developmental stages from birth to adulthood. We found that VPA-treated rats exhibited behavioral abnormalities relevant to autism, including delayed nervous reflex development, altered motor coordination, delayed sensory development, autistic-like and anxiety behaviors and impaired spatial learning and memory. We also found that VPA rats had the decreased expression of GAD67 in the hippocampus (HC) and cerebellum from childhood to adulthood, while decreased GAD67 expression of the temporal cortex (TC) was only observed in adulthood. Conversely, GAD67 expression was increased in the prefrontal cortex (PFC) from adolescence to adulthood. The dysregulated GAD67 expression could alter the excitatory-inhibitory balance in the cerebral cortex, HC and cerebellum. Our findings indicate an impaired GABAergic system could be a major etiological factor occurring in the cerebral cortex, HC and cerebellum of human cases of autism, which suggests enhancement of GABA signaling would be a promising therapeutic target for its treatment.

Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder.

We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. Our work validates the use of the VPA model in the quest for evaluating suitable therapeutic targets for improving attentional performance.

Altered expression of circadian rhythm and extracellular matrix genes in the medial prefrontal cortex of a valproic acid rat model of autism

Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders caused by complex interplay between various genes and environmental factors during embryonic development. Changes at the molecular, cellular and neuroanatomical levels are especially evident in the medial prefrontal cortex (mPFC) of ASD patients and are particularly contributing to social impairments. In the present study we tested the hypothesis that altered neuronal development and plasticity, as seen in the mPFC of ASD individuals, may result from aberrant expression of functionally connected genes. Towards this end, we combined transcriptome sequencing and computational gene ontology analysis to identify the molecular networks impaired in the mPFC of a valproic acid (VPA) rat model of autism. This investigation identified two subsets of genes differentially expressed in the mPFC of VPA rats: one group of genes being functionally involved in the regulation of the circadian rhythm, while the second group encompasses a set of differentially expressed collagen genes acting within the extracellular matrix. Ultimately, our integrated transcriptome analysis identified a distinct subset of altered gene networks in the mPFC of VPA rats, contributing to our understanding of autism at the molecular level, thus providing novel insight into the genetic alterations associated with this neurodevelopmental disorder.

Valproic Acid Prevents Renal Dysfunction and Inflammation in the Ischemia-Reperfusion Injury Model.

Ischemia-reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). At present, there are no effective therapies to prevent AKI. The aim of this study was to analyse whether valproic acid (VPA), a histone deacetylase inhibitor with anti-inflammatory properties, prevents renal IRI. Male Wistar rats were divided into three groups: SHAM rats were subjected to a SHAM surgery, IRI rats underwent bilateral renal ischemia for 45 min, and IRI + VPA rats were treated with VPA at 300 mg/kg twice daily 2 days before bilateral IRI. Animals were euthanized at 48 hours after IRI. VPA attenuated renal dysfunction after ischemia, which was characterized by a decrease in BUN (mg/dL), serum creatinine (mg/dL), and FENa (%) in the IRI + VPA group (39 ± 11, 0.5 ± 0.05, and 0.5 ± 0.06, resp.) compared with the IRI group (145 ± 35, 2.7 ± 0.05, and 4.9 ± 1, resp.; p < 0.001). Additionally, significantly lower acute tubular necrosis grade and number of apoptotic cells were found in the IRI + VPA group compared to the IRI group (p < 0.001). Furthermore, VPA treatment reduced inflammatory cellular infiltration and expression of proinflammatory cytokines. These data suggest that VPA prevents the renal dysfunction and inflammation that is associated with renal IRI.

Impaired Processing in the Primary Auditory Cortex of an Animal Model of Autism.

Autism is a neurodevelopmental disorder clinically characterized by deficits in communication, lack of social interaction and repetitive behaviors with restricted interests. A number of studies have reported that sensory perception abnormalities are common in autistic individuals and might contribute to the complex behavioral symptoms of the disorder. In this context, hearing incongruence is particularly prevalent. Considering that some of this abnormal processing might stem from the unbalance of inhibitory and excitatory drives in brain circuitries, we used an animal model of autism induced by valproic acid (VPA) during pregnancy in order to investigate the tonotopic organization of the primary auditory cortex (AI) and its local inhibitory circuitry. Our results show that VPA rats have distorted primary auditory maps with over-representation of high frequencies, broadly tuned receptive fields and higher sound intensity thresholds as compared to controls. However, we did not detect differences in the number of parvalbumin-positive interneurons in AI of VPA and control rats. Altogether our findings show that neurophysiological impairments of hearing perception in this autism model occur independently of alterations in the number of parvalbumin-expressing interneurons. These data support the notion that fine circuit alterations, rather than gross cellular modification, could lead to neurophysiological changes in the autistic brain.

Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.

Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits.

Study of the serum levels of polyunsaturated fatty acids and the expression of related liver metabolic enzymes in a rat valproate-induced autism model

To investigate whether the decreased level of serum polyunsaturated fatty acids (PUFAs) in patients with autism is associated with the expression of related liver metabolic enzymes, we selected rats that were exposed to valproic acid (VPA) on embryonic day 12.5 (E12.5) as a model of autism. We observed the serum levels of PUFAs and the expression of related liver metabolic enzymes, including Δ5-desaturase, Δ6-desaturase and elongase (Elovl2), in VPA-exposed and control rats on postnatal day 35 (PND35) and conducted sex dimorphic analysis. We found that the levels of serum PUFAs and related liver metabolic enzymes in the VPA rats were significantly reduced, in association with autism-like behavioral changes, the abnormal expression of apoptosis-related proteins and hippocampal neuronal injury, compared to the control rats and showed sex difference in VPA group. This finding indicated that rats exposed to VPA at the embryonic stage may exhibit reduced synthesis of serum PUFAs due to the down-regulation of liver metabolic enzymes, thereby inducing nervous system injury and behavioral changes, which is affected by sex in the meantime.

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

Autism spectrum disorders (ASD) are a group of developmental disabilities characterized by impaired social interaction, communication deficit and repetitive and stereotyped behaviors. Neuroinflammation and synaptic alterations in several brain areas have been suggested to contribute to the physiopathology of ASD. Although the limbic system plays an important role in the functions found impaired in ASD, reports on these areas are scarce and results controversial. In the present study we searched in the medial prefrontal cortex (mPFC) and hippocampus of rats exposed to the valproic acid (VPA) model of ASD for early structural and molecular changes, coincident in time with the behavioral alterations. After confirming delayed growth and maturation in VPA rats, we were able to detect decreased exploratory activity and social interaction at an early time point (postnatal day 35). In mPFC, although typical cortical column organization was preserved in VPA animals, we found that interneuronal space was wider than in controls. Hippocampal CA3 (cornu ammonis 3) pyramidal layer and the granular layer of the dentate gyrus both showed a disorganized spatial arrangement in VPA animals. Neuronal alterations were accompanied with increased tomato lectin and glial fibrillary acidic protein (GFAP) immunostainings both in the mPFC and hippocampus. In the latter region, the increased GFAP immunoreactivity was CA3 specific. At the synaptic level, while mPFC from VPA animals showed increased synaptophysin (SYN) immunostaining, a SYN deficit was found in all hippocampal subfields. Additionally, both the mPFC and the hippocampus of VPA rats showed increased neuronal cell adhesion molecule (NCAM) immunostaining together with decreased levels of its polysialylated form (PSA-NCAM). Interestingly, these changes were more robust in the CA3 hippocampal subfield. Our results indicate that exploratory and social deficits correlate with region-dependent neuronal disorganization and reactive gliosis in the mPFC and hippocampus of VPA rats. While microgliosis is spread in these two limbic areas, astrogliosis, although extended in the mPFC, is circumscribed to the CA3 hippocampal subfield. Our work indicates that neuroinflammation and synaptic alterations do coexist in VPA rats, making this model suitable for studying novel aspects of neuron-glia interactions. Moreover, it suggests that the mPFC and hippocampus might behave differently in the context of the local hyperconnectivity and synaptic hypotheses of autism.

Abnormalities in BDNF/TrkB/PI3K signaling pathways in autism (728.3)

Cortical connectivity and spine abnormalities may account for clinical features of autism. BDNF, a key spine regulator, exhibits altered isoform balance in autism. Here, we investigated whether BDNF receptors and their signaling pathways are disrupted in post‐mortem fusiform gyrus from subjects with autism compared to controls and in the valproic acid (VPA)‐induced rat model of autism.Protein levels were examined by Western blot in 11 autism vs 13 control subjects and in lateral temporal neocortices of VPA rats vs controls. Reduced TrkB, PI3K, Akt, mTOR, phospho‐mTOR, p70S6K, eIF4B and PSD‐95 and a trend towards increased truncated TrkB and p75NTR, but no changes in 4E‐BP1 or eIF4E, were found in autism subjects versus controls. Similar deficits were observed in VPA rats, although total and phospho‐4E‐BP1 were decreased in these rats.These findings suggest imbalances in BDNF/TrkB/PI3K and proBDNF/p75NTR signaling in autism which could lead to spine defects. Reduced Akt‐mTOR protein and signaling, suggesting spine protein synthesis deficits, were observed in both autism and VPA rats, despite minor differences in down‐regulated signaling cascades. The resulting spine defects might lead to loss of excitatory synapses/decreased PSD‐95 in autism. Reduced excitatory synapses might perturb cortical circuitry, contributing to autism’s cognitive and behavioral deficits.