**6. Concluding remarks and scientific challenges**

Astrocytes are the major cell type in the central nerve system (CNS) and provide a variety of critical supportive functions that maintain neuronal homeostasis, participating of the synapse and the glutamatergic metabolism [112]. These cells become reactive in VPA group, charac‐ terized by up-regulation of GFAP and apparently show higher number of processes than the

Seven Fresh-frozen *post mortem* tissues from individuals with autism and CSF from six living autistic patients were investigated for cytokine protein profiling [113]. This study shows an active neuroinflammatory process in the cerebral cortex, white matter, and notably in the cerebellum. Immunocytochemical studies showed marked activation of microglia and astroglia. The cytokine profiling indicated that the macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, both derived from neuroglia were the most prevalent cytokines in brain tissues. We presumed that microglia/macrophage-derived pro-inflamma‐ tory cytokines regulate the transition of astrocytes into reactive astrogliosis. Nevertheless, the mechanisms which regulate the level of astroglial cell activity in the hippocampus from VPA

**HippocampusP15** Control VPA

**Figure 2.** Astrocyte immunoreactive to GFAP in hippocampus from rats. A. Representative image from control group,

Glutamatergic excitatory synapses are the major type of synapses in the brain and it was found that glutamate metabolism is altered in autistic CNS, particularly the glutamate receptors AMPA, NMDA and mGluR5 [114]. In agreement, rats exposed *in utero* to VPA show impair‐ ments in excitatory/inhibitory brain balance [78]. In this context, impairment in excitatory and inhibitory signaling during certain periods of development is proposed to be involved in the

Although social impairments are one of the most important features observed in autism, patients present several other symptoms, including motor disturbances. Motor stereoty‐ pies are part of the so called autism triad of impairments, but hypotonia, motor apraxia,

control cells as demonstrated by the squares in A and B.

A B

B. Representative image from VPA group. Scale bar = 50 μm

autism pathophysiology [115].

autism model need to be investigated.

152 Recent Advances in Autism Spectrum Disorders - Volume I

The spectrum of autism comprises a multifactorial group of disorders, with phenotypic diversity related to the symptoms and increasing prevalence. One of the major challenges of cognitive neuroscience is to understand how changes in the structural properties of the brain affect the plasticity exhibited whenever a person develops, ages, learns a new skill, make social interaction or adapts to a disease. In ASD, it is necessary studies in this field attempting to explain and understand the trigger of autism. In this context, it is not easy to find a single animal model able to captures the entire molecular and cellular alterations observed in patients with ASD.

Studies of *in utero* interventions in the search for animal models of autism, together with the study of potential clinical markers to ASD are innovative and may generate strategies aiming (a) the prevention of autism; (b) the construction of laboratory kits as new tools to improve and anticipate diagnosis; (c) the study of neuroglial plasticity; (d) the search for new clues to unravel the etiology of ASD. Challenged by these complexities, it is necessary to evaluate the most representative animal model to which a research group may address its questions. Considering that neuroimmune responses are influenced by the host, the role of possible neuroinflammation triggered by environmental factors in utero followed by neuroglial alterations in the litters remain an important issue to be investigated.

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Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model

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The present chapter summarizes findings obtained in rodents exposed *in utero* to VPA which present important similarities to autism features, supporting it as a valuable experimental model to study neurodevelopmental alterations induced by VPA as an environmental risk factor.
