A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by the hyperreactivity and hyperplasticity found in the lateral amygdala, which may in turn be due to a deficit in the inhibitory system of the amygdala. We hypothesize an 'aversive world' syndrome that could, even if not a primary cause of the disorder itself, underlie some core symptoms in autism, such as impairments in social interactions and resistance to rehabilitation.

Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome. Keywords: autism, microcircuit, connectivity, plasticity, neocortex, amygdala, valproic acid INTRODUCTIONAutism as a syndrome was first described by Leo Kanner, a child psychologist, in 1943. His initial description, based on 11 case studies emphasized ". . .an innate inability to form the usual, biologically provided affective contact with other people." For a long time, autism was thought to be a consequence of bad parenting and the "refrigerator mother" theory (Bettelheim, 1967) lasted from the 1950s well beyond the 1970s. Bernard Rimland (Rimland, 1964) and Michael Rutter (Rutter, 1968) established empirically that the parents of autistic children were not different in their parenting from the parents of non-autistic controls and helped building a case for a neurobiological basis of autism. Autism is now recognized as a neurodevelopmental disorder manifesting within the first 3 years after birth and progressively worsening in the course of life. The core symptoms are impairments of sociability, communicative skills and imagination, together with stereotypic behaviors and repetitive tendencies (DSM-IV, 1994). At the cognitive level, all autistic children seem to display some form of abnormality in perception, attention, and memory (Ben Shalom, 2003;Dakin and Frith, 2005;Sanders et al., 2007).Genetic analyses have revealed that autism is a polygenetic disorder where any one or more set of genes can predispose toward, but no one gene has been...

Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain unknown. We therefore studied plasticity-related mechanisms in the neocortex of 2-weekold rats prenatally exposed to VPA and tested for changes in glutamate-mediated transmission and plasticity in the neocortex. We found a selective overexpression of NR2A and NR2B subunits of NMDA receptors, as well as the commonly linked kinase calcium/ calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes increased plasticity in the neocortex. Enhanced plasticity introduces a surprising perspective to the potential molecular and synaptic mechanisms involved in children prenatally exposed to VPA.autism ͉ in vitro electrophysiology ͉ plasticity ͉ somatosensory cortex ͉ NMDA receptors A utism is a developmental disorder of neurological origin primarily affecting social cognition. Its etiology has not yet been clarified, but genetic and environmental contributions to neurodevelopmental alterations either cause or confer vulnerability to this disorder (1). The teratogens that have been most clearly linked to autism include thalidomide (2) and valproic acid (VPA) (3-7). These drugs can cause diverse birth defects, but over a narrow time window of vulnerability (days 20-24 of human pregnancy), they have a higher likelihood of causing autism (8, 9). The core symptoms of autism, first identified by Leo Kanner in 1943 (10), are centered around inappropriate social interaction, poor or no language development, enhanced sensory sensitivity, repetitive behaviors, attention abnormalities, and resistance to novel environments (11). Most affected children tend to have a lower IQ than their peers, but the extent to which the communication deficit has clouded these assessments is not clear. A fraction of autistic children are considered high functioning, with unusually powerful memory capabilities, and children who do solve the communication handicap are often found to have unusual learning and memory capabilities (12-17). There are currently no potential molecular and synaptic candidates for the learning and memory alterations found in autistic children.Recent studies are focusing more on animal models of autism, which could provide the only means of rapidly exploring molecular, synaptic, and cellular candidates linked to the disorder. The rat VPA model is one example of an insult-based model that is being increasingly explored (9, 18-21). Offspring of pregnant rats exposed to a single injection of VPA display some of the gross anatomical changes (18,22) and core behavioral symptoms observed in autism, such as impaired social inter...

The prefrontal cortex has been extensively implicated in autism to explain defi cits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to signifi cantly more neighbouring neurons than in controls. These excitatory connections are more plastic displaying enhanced long-term potentiation of the strength of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms. We propose that a number of defi cits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyperfunctional prefrontal cortex.

Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render cortical modules more sensitive to stimulation and once activated, more autonomous, isolated, and more difficult to command. This could underlie some of the core symptoms observed in humans prenatally exposed to valproic acid.