TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex

• Published in: Experimental neurology 2024-03, Vol.373, p.114652-114652, Article 114652
• Main Authors: Francis-Oliveira, José, Higa, Guilherme Shigueto Vilar, Viana, Felipe José Costa, Cruvinel, Emily, Carlos-Lima, Estevão, da Silva Borges, Fernando, Zampieri, Thais Tessari, Rebello, Fernanda Pereira, Ulrich, Henning, De Pasquale, Roberto
• Format: Article
• Language: English
• Subjects: 5HT1A receptor; Animals; Antidepressive Agents - pharmacology; Cerebral Cortex; Depression; Hippocampus - physiology; Long-Term Synaptic Depression - physiology; LTD; Neuronal Plasticity - physiology; Potassium Channels, Tandem Pore Domain - genetics; Prefrontal Cortex; Prelimbic cortex; Rats; Synaptic plasticity; Synaptic Transmission - physiology; TREK-1
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2023.114652

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 5HT1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT1A 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. •In the prelimbic cortex, TREK-1 reduces synaptic excitatory responses induced by 5HT1A activation.•5HT1A receptor activation decreases excitatory and inhibitory evoked responses in the prelimbic cortex.•TREK-1 inhibition promotes TBS-induced LTD in the prelimbic cortex when acting in synergy with 5HT1A.•TREK-1 inhibition reduces synaptic excitation and facilitates LTD in animals subjected to early life stress.