Synaptic Plasticity Modulation by TREK-1 and 5HT1A in Postnatal Chronic Stress.

Author(s)

José Francis de Oliveira

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2020-05-29

Examining board members

Roberto de Pasquale; Fernando Rodrigues de Moraes Abdulkader; Manoel de Arcisio Miranda Filho; Carolina Demarchi Munhoz

• Advisor: Roberto de Pasquale

Abstract

Stress is associated to the etiology of several diseases, such as anxiety and depression, and women are more vulnerable to develop depression. Early-life stress, including adolescence, can lead to permanent effects at adulthood, related to neuropsychiatric illnesses development. The serotonergic system has a fundamental role in the stress response modulation, being the serotonergic receptor 5HT1A one of the most important in the brain stress circuitry. Serotonin is a neurotransmitter important for synaptic plasticity, which is a key neuronal event impaired in depression, and this neurotransmitter can act on potassium channels in the membrane and alter neuronal excitability. TREK-1 potassium channels had been associated to stress related diseases, and knockout mice for these channels are depression resilient. This study demonstrate early-life stress, present in the Maternal Separation (MS) model, induced depressive-like behavior in infant rats, in a sex-dependent way, being females more vulnerable to MS. Correlated changes in 5HT1A and TREK1 expression occur in the entorhinal cortex in infant males, and are associated to a phenotype relatively resilient do depression, while correlated changes in the dentate gyrus of the hippocampus are associated to vulnerability to depression in infant females. 5HT1A activation in the prelimbic cortex is sufficient to evoke a long-term synaptic depression (LTD), and this effect is dependent on the opening of TREK-1 channels. TREK-1 blockage is enough to elicit an LTD in the PL through a postsynaptic mechanism, however MS alters the components of synaptic plasticity associated to this blockage, as MS animals also present a presynaptic component for this LTD. In conclusion, early-life stress produced by MS can induce increased neuropsychiatric vulnerability in females, modifying 5HT1A and TREK-1 expression in the corticolimbic circuitry, resulting in altered synaptic plasticity in the prelimbic cortex and behavioral changes. (AU)

• FAPESP's process: 16/09116-0 - Evaluation of TREK-1 physiological role in neural stress modulation
• Grantee: José Francis de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate