TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex

José Francis-Oliveira; Guilherme Shigueto Vilar Higa; Felipe José Costa Viana; Emily Cruvinel; Estevão Carlos-Lima; Fernando da Silva Borges; Thais Tessari Zampieri; Fernanda Pereira Rebello; Henning Ulrich; Roberto De Pasquale

doi:10.1016/j.expneurol.2023.114652

TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex

Exp Neurol. 2024 Mar:373:114652. doi: 10.1016/j.expneurol.2023.114652. Epub 2023 Dec 15.

Affiliations

¹ Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, SP 05508-000, Brazil; Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
² Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, SP 05508-000, Brazil; Departamento de Bioquímica, Instituto de Química (USP), Butantã, SP 05508-900, Brazil; Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, SP 09210-580, Brazil.
³ Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, SP 05508-000, Brazil.
⁴ Department of Physiology & Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA.
⁵ Departamento de Bioquímica, Instituto de Química (USP), Butantã, SP 05508-900, Brazil.
⁶ Laboratório de Neurofisiologia, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Butantã, SP 05508-000, Brazil. Electronic address: robertode@usp.br.

PMID: 38103709
DOI: 10.1016/j.expneurol.2023.114652

Abstract

Synaptic plasticity is one of the putative mechanisms involved in the maturation of the prefrontal cortex (PFC) during postnatal development. Early life stress (ELS) affects the shaping of cortical circuitries through impairment of synaptic plasticity supporting the onset of mood disorders. Growing evidence suggests that dysfunctional postnatal maturation of the prelimbic division (PL) of the PFC might be related to the emergence of depression. The potassium channel TREK-1 has attracted particular interest among many factors that modulate plasticity, concerning synaptic modifications that could underlie mood disorders. Studies have found that ablation of TREK-1 increases the resilience to depression, while rats exposed to ELS exhibit higher TREK-1 levels in the PL. TREK-1 is regulated by multiple intracellular transduction pathways including the ones activated by metabotropic receptors. In the hippocampal neurons, TREK-1 interacts with the serotonergic system, one of the main factors involved in the action of antidepressants. To investigate possible mechanisms related to the antidepressant role of TREK-1, we used brain slice electrophysiology to evaluate the effects of TREK-1 pharmacological blockade on synaptic plasticity at PL circuitry. We extended this investigation to animals subjected to ELS. Our findings suggest that in non-stressed animals, TREK-1 activity is required for the reduction of synaptic responses mediated by the 5HT_1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT_1A receptor stimulation. On the other hand, in ELS animals, TREK-1 blockade reduces synaptic transmission and facilitates LTD expression. These results indicate that TREK-1 inhibition stimulates synaptic plasticity in the PL and this effect is more pronounced in animals subjected to ELS during postnatal development.

Keywords: 5HT(1A) receptor; Depression; LTD; Prelimbic cortex; Synaptic plasticity; TREK-1.

MeSH terms

Animals
Antidepressive Agents / pharmacology
Cerebral Cortex
Hippocampus / physiology
Long-Term Synaptic Depression / physiology
Neuronal Plasticity* / physiology
Potassium Channels, Tandem Pore Domain* / genetics
Prefrontal Cortex
Rats
Synaptic Transmission / physiology

Substances

potassium channel protein TREK-1
Potassium Channels, Tandem Pore Domain
Antidepressive Agents