Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism.

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 µm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12-15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 µM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism.

The prefrontal cortex has been extensively implicated in autism to explain deficits 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 significantly 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 deficits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyper-functional prefrontal cortex.

Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid.

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.

Abnormal fear conditioning and amygdala processing in an animal model of autism.

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.

Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid.

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-week-old 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.

[Oral complications in patients with head and neck cancer after radio-chemotherapy. Mucositis and xerostomia]. / Complicanze orali in pazienti affetti da carcinoma del cavo orale e sottoposti a radio e chemioterapia. Mucositi e xerostomia.

Surgery, chemotherapy and radiotherapy are different therapeutical options for the management of the head and neck cancers. Their indication is strictly relate to some parameters (macro and microscopic characteristics of the tumor, the patient's general health and the remaining expectations of the life of the patients). Surgical treatment of the cancer, even if it represents the most radical approach and with the most therapeutical index, it always can't be practicable, since, often, it is associated to imposing aesthetical and functional alterations of the interested district. Chemotherapic agents are among the drugs with the lower therapeutical index, that are able to cause side effects, mainly due to the immunosuppression. About radiations, side effects could be indicates as immediates or acutes, and backward or chronic. Among the acute manifestations are enumerated: xerostomia, mucositis, bacterial infections, dysgeusia, dysphagia; among chronic forms: hyposalivation-xerostomia, caries, telangiectasis, infections, osteoradionecrosis, trismus, muscular fibrosis, necrosis of the soft tissues. Mucositis and xerostomia are the most common side effects, and they are a potential source of life-threatening infections. Few interventions are of proven efficacy to reducing severity and duration of mucositis, and there are no universally accepted treatment protocols, but research activity is increasing because of the upward recognition of the importance of mucositis, that need a complex and multidisciplinary clinical management.

The intense world syndrome--an alternative hypothesis for autism.

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.