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Autism spectrum disorders (ASD) are characterized by deficits in social interaction, language and communication impairments and repetitive and stereotyped behaviors, with involvement of several areas of the central nervous system (CNS), including hippocampus. Although neurons have been the target of most studies reported in the literature, recently, considerable attention has been centered upon the functionality and plasticity of glial cells, particularly astrocytes. These cells participate in normal brain development and also in neuropathological processes. The present work investigated hippocampi from 15 (P15) and 120 (P120) days old male rats prenatally exposed to valproic acid (VPA) as an animal model of autism. Herein, we analyzed astrocytic parameters such as glutamate transporters and glutamate uptake, glutamine synthetase (GS) activity and glutathione (GSH) content. In the VPA group glutamate uptake was unchanged at P15 and increased 160% at P120; the protein expression of GLAST did not change neither in P15 nor in P120, while GLT1 decreased 40% at P15 and increased 92% at P120; GS activity increased 43% at P15 and decreased 28% at P120; GSH content was unaltered at P15 and had a 27% increase at P120. These data highlight that the astrocytic clearance and destination of glutamate in the synaptic cleft might be altered in autism, pointing out important aspects to be considered from both pathophysiologic and pharmacological approaches in ASD.

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Diabetes mellitus (DM) is a metabolic disorder associated with micro- and macrovascular alterations that contribute to the cognitive impairment observed in diabetic patients. Signs of breakdown of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been found in patients and animal models of DM. Breakdown of the BBB and BCSFB can lead to disruptions in cerebral homeostasis and eventually neural dysfunction and degeneration. However, our understanding of the biochemistry underlying barrier protein modifications is incomplete. Herein, we evaluated changes in the levels of specific proteins in the BBB (occludin, claudin-5, ZO-1, and aquaporin-4) and BCSFB (claudin-2 and aquaporin-1) in the hippocampus of diabetic rats, and we also investigated the functional alterations in these barriers. In addition, we evaluated the ability of exendin-4 (EX-4), a glucagon-like peptide-1 agonist that can cross the BBB to reverse the functional and biochemical modifications observed in these animals. We observed a decrease in BBB proteins (except ZO-1) in diabetic rats, whereas the EX-4 treatment recovered the occludin and aquaporin-4 levels. Similarly, we observed a decrease in BCSFB proteins in diabetic rats, whereas EX-4 reversed such changes. EX-4 also reversed alterations in the permeability of the BBB and BCSFB in diabetic rats. Additionally, altered cognitive parameters in diabetic rats were improved by EX-4. These data further our understanding of the alterations in the central nervous system caused by DM, particularly changes in the proteins and permeability of the brain barriers, as well as cognitive dysfunction. Furthermore, these data suggest a role for EX-4 in therapeutic strategies for cognitive dysfunction in DM.

Based on the concept of the tripartite synapse, we have reviewed the role of glucose-derived compounds in glycolytic pathways in astroglial cells. Glucose provides energy and substrate replenishment for brain activity, such as glutamate and lipid synthesis. In addition, glucose metabolism in the astroglial cytoplasm results in products such as lactate, methylglyoxal, and glutathione, which modulate receptors and channels in neurons. Glucose has four potential destinations in neural cells, and it is possible to propose a crossroads in “X” that can be used to describe these four destinations. Glucose-6P can be used either for glycogen synthesis or the pentose phosphate pathway on the left and right arms of the X, respectively. Fructose-6P continues through the glycolysis pathway until pyruvate is formed but can also act as the initial compound in the hexosamine pathway, representing the left and right legs of the X, respectively. We describe each glucose destination and its regulation, indicating the products of these pathways and how they can affect synaptic communication. Extracellular L-lactate, either generated from glucose or from glycogen, binds to HCAR1, a specific receptor that is abundantly localized in perivascular and post-synaptic membranes and regulates synaptic plasticity. Methylglyoxal, a product of a deviation of glycolysis, and its derivative D-lactate are also released by astrocytes and bind to GABAA receptors and HCAR1, respectively. Glutathione, in addition to its antioxidant role, also binds to ionotropic glutamate receptors in the synaptic cleft. Finally, we examined the hexosamine pathway and evaluated the effect of GlcNAc-modification on key proteins that regulate the other glucose destinations.

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