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Kv3.1 channel as a new target for schizophrenia treatment

Grant number: 20/04241-6
Support type:Scholarships in Brazil - Master
Effective date (Start): June 01, 2020
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Felipe Villela Gomes
Grantee:Andreza Manzato Cavichioli
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets, AP.JP

Abstract

Psychiatric disorders are the leading cause of disability related to non-fatal chronic diseases, representing a major challenge for the entire medical and scientific community. Among these disorders, schizophrenia is considered the most disabling medical condition, affecting the quality of life of affected individuals and their families. Despite several scientific advances, the understanding of the mechanisms underlying the pathophysiology of schizophrenia is not clear. It is known that socio-environmental risk factors, such as stress, play a fundamental role in the development of this disease. Studies indicate that exposure to stress during critical periods of development, such as adolescence, results in a hyperdopaminergic state indicated by increased activity of the ventral tegmental area (VTA) dopamine system. The hyperfunction of the dopamine system is one of the main pathological findings in schizophrenia and is associated with the psychotic symptoms in the disease. However, evidence suggest that the hyperfunction of this system may be a consequence of changes in the activity of afferent brain regions, such as the ventral hippocampus, which also regulates stress responsivity. Changes in the activity of the ventral hippocampus in schizophrenia are related to a dysfunction in the synchronized activity of GABAergic interneurons expressing the calcium-binding protein parvalbumin (PV) and glutamatergic pyramidal neurons. PV-positive interneurons have a high firing frequency and form a cellular network capable of synchronizing the excitatory state of pyramidal neurons and, then, controlling the information that flows from these neurons, a process called excitatory-inhibitory balance. It is known that one of the most consistent findings in the post-mortem brain of schizophrenia patients is the reduced PV expression in the hippocampus. It is thought that a decrease in PV expression in the hippocampus leads to an increase in the activity of the pyramidal neurons of this structure, which would result in an enhanced VTA dopamine system activity. Therefore, pharmacological strategies that aim to restore abnormalities in the excitatory-inhibitory balance could be effective in the treatment of schizophrenia. The Kv3.1 potassium channels expressed in PV interneurons play an important role in the regulation of the fast-spiking activity of these interneurons and, consequently, in the synchronized activity with pyramidal neurons. Thus, the modulation of the activity of these channels could restore functional losses in the excitatory-inhibitory balance. Thus, drugs acting through the positive modulation of these channels, such as levetiracetam, may be a pharmacological alternative in the treatment of schizophrenia. To test this hypothesis, the effects of levetiracetam on behavioral (anxiety response, cognitive impairment and dopaminergic hyperresponsiveness) and electrophysiological changes (increased activity of dopaminergic neurons in the VTA and pyramidal neurons in the ventral hippocampus) associated with schizophrenia induced by adolescent stress exposure will be evaluated. Finally, in this project, we aim to investigate a new and potentially more effective pharmacological target for the treatment of schizophrenia that could improve the quality of life of patients and their family members who have their lives so affected by this psychiatric disorder. (AU)