ROLE OF AMPA RECEPTORS IN PHYSIOPATHOLOGICAL CONDITIONS IN THE CENTRAL NERVOUS SYSTEM

Description

AMPA receptors play a key role in synaptic glutamatergic transmission in both physiological and pathological conditions of the central nervous system. Particularly, I have tried to analyze and to give some answers on aspects that are still unexplored or controversial using synaptosomes (pinched off nerve terminals) as experimental model. As a first approach I focused on the composition of the GluA subunits, which is a requisite to encompass the role of AMPA receptors in the physiological conditions but also in neurological disorders. By using the "immuno- pharmacological approach", which consists in using antibodies recognizing the outer sequences of the target protein as a pharmacological tool, I propose that cortical AMPA autoreceptors consist of GluA2-GluA3 subunits assembly, which move in-out synaptosomal plasma membranes in a constitutive manner. The commercially available anti-GluA2 and anti-GluA3 antibodies hugely facilitated the releasing activity of the AMPA autoreceptors by stabilizing them in plasma membranes. Interestingly, the consequent presence of the antigen-antibody complex in synaptosomal plasma membranes caused the activation of complement through the classic pathway, then reinforcing the complement-induced evoked releasing activity of the immune complex in these terminals. The results unveiled therefore a complement-dependent and a complement-independent pathway that could account for central derangements and excitotoxic events occurring during central autoimmune diseases typified by anti-GluA autoantibodies overproduction. It is the case of patients suffering from the frontotemporal dementia (FTD) that have elevated levels of circulating anti-GluA3 autoantibodies. Contrary to expectation, however, the incubation of mice cortical synaptosomes with FTD patients' CSF (cerebrospinal fluid) positive for anti-GluA3 autoantibodies causes the reduction of the glutamate release evoked by the agonist AMPA, instead of the predicted amplification. Further studies are required to address the point. AMPA receptors are also potential targets of detrimental events in stress-related diseases, which are recapitulated by several animal models, including the perinatal restrain stress (PRS) rat model. By using this model, I investigated the long-term programming effects of PRS on the glutamatergic synapse in males and females. I demonstrated that male PRS rats displayed a reduced expression of GluA2 and GluA3 subunits in the dorsal hippocampus and prefrontal cortex in old age rats (20-22 months), in line with their impaired performance in the behavioral test. These results confirmed that the impaired glutamatergic transmission lie at the core of the pathological phenotype induced by PRS. Remarkably, the long-term programming effects triggered by PRS are strictly sex-dependent. Particularly, PRS mainly affects males whereas females seem to be protected against the detrimental effects triggered by early life stress. Taken together these results strengthened the importance of understanding more about the role of AMPA receptors subunits in the brain functions.

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