Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and nonverbal communication, and stereotyped, repetitive patterns of behaviors and interests. Recently, a new rodent model of autism was created by exposure of rat fetuses to valproic acid (VPA) on the 12.5th day of gestation (VPA rats). The model has striking anatomical, pathological, and etiological similarities to human data; however, it has not been characterized behaviorally. In order to determine if VPA rats present behavioral aberrations observed in autism, their behavior was extensively evaluated in a battery of tests. The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity, and (4) decreased number of social behaviors and increased latency to social behaviors. In addition, VPA rats showed delayed maturation, lower body weight, delayed motor development, and attenuated integration of a coordinated series of reflexes, delayed nest-seeking response mediated by olfactory system, and normal negative geotaxis. Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia. Our results bring further support to validity of the proposed VPA animal model of autism, suggesting similarities between the observed pattern of behavioral alterations in VPA rats and features of disturbed behavior in autistic patients.

ABSTRACT

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SummaryA minority of individuals experiencing traumatic events develop anxiety disorders. The reason for the lack of correspondence between the prevalence of exposure to psychological trauma and the development of anxiety is unknown. Extracellular proteolysis contributes to fear-associated responses by facilitating neuronal plasticity at the neuron-matrix interface1-4. Here we show that the serine protease neuropsin is critical for stress-related plasticity in the amygdala by regulating the dynamics of EphB2/NMDA receptor interaction, the expression of Fkbp5 and anxiety-like behaviour. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala causing dissociation of EphB2 from the NR1-subunit of NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2/NR1 interaction enhances NMDA receptor current, induces the Fkbp5 gene expression and enhances behavioural signatures of anxiety. Upon stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1 resulting in a static EphB2/NR1 interaction, attenuated induction of the Fkbp5 gene and low anxiety. The behavioural response to stress can be restored by intra-amygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wild-type animals. Our findings establish a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.

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We investigated the efficacy of local intraplantar (i.pl.) injection of peptide and non-peptide mu-, delta- and kappa-opioid receptor agonists in rat models of inflammatory and neuropathic pain. Locally applied agonists dose-dependently reduced formalin-induced flinching of the inflamed paw and induced antiallodynic and antihyperalgesic effects in sciatic nerve ligation-induced neuropathic pain. These effects were mediated by peripheral opioid receptors localized at the side of tissue/nerve injury, as was demonstrated by selective and non-selective opioid receptors antagonists. The ED(50) dose range of mu- and kappa-agonists required to induce analgesia in neuropathy was much higher than the ED(50) for inflammation; moreover, only delta-agonists were effective in the same dose range in both pain models. Additionally, effective antinociception was achieved at a lower dose of peptide, compared to non-peptide, opioids. Such findings support the use of the peripheral administration of opioid peptides, especially delta-agonists, in treating chronic pain. Furthermore, in order to assess whether adaptations in the expression of opioid genes could underlie the clinical observation of reduced opioid effectiveness in neuropathic pain, we analyzed the abundance of opioid transcripts in the spinal cord and dorsal root ganglia (DRG) during the neuropathy and inflammation. Nerve injury down-regulated mRNA for all types of opioid receptors in the DRG, which is predicted to decrease in the synthesis of opioid receptors to possibly account for the reduced effectiveness of locally administered opioids in neuropathy. The obtained results differentiate inflammatory and neuropathic pain and provide a novel insight into the peripheral effectiveness of opioids in both types of pain.

Environmental enrichment has been repeatedly shown to affect multiple aspects of brain function, and is known to improve cognitive, behavioral, and histopathological outcome after brain injuries. The purpose of the present experiments was to determine the effect of an enriched environment on behavioral aberrations observed in male rats exposed to valproic acid on day 12.5 of gestation (VPA rats), and proposed on the basis of etiological, anatomical, and behavioral data as an animal model of autism. Environmental enrichment reversed almost all behavioral alterations observed in the model. VPA rats after environmental enrichment (VPA-E) compared to VPA rats reared in standard conditions have higher sensitivity to pain and lower sensitivity to nonpainful stimuli; stronger acoustic prepulse inhibition; lower locomotor, repetitive/stereotypic-like activity, and enhanced exploratory activity; decreased anxiety; increased number of social behaviors; and shorter latency to social explorations. In comparison with control animals (Con), VPA-E rats exhibited increased number of pinnings in adolescence and social explorations in adulthood, and were less anxious in the elevated plus maze. Similar differences in social behavior and anxiety were observed between control rats exposed to environmental enrichment (Con-E) and control group reared in standard conditions. These results suggest that postnatal environmental manipulations can counteract the behavioral alterations in VPA rats. We propose environmental enrichment as an important tool for the treatment of autism spectrum disorders.

The transcriptional response to six commonly-abused drugs was assessed in the mouse brain revealing common modules of drug-induced genes.