T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex

Abstract

Abnormalities in thyroid hormones (TH) availability and/or metabolism have been hypothesized to contribute to Alzheimer's disease (AD) and to be a risk factor for stroke. Recently, 3-iodothyronamine (T₁AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T₁AM has been demonstrated to rescue the β-Amyloid dependent LTP impairment in the entorhinal cortex (EC), a brain area crucially involved in learning and memory and early affected during AD. In the present work, we have investigated the effect of T₁AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T₁AM (5 μM) was capable of preventing ischemia-induced synaptic depression and that this protective effect was mediated by the trace amine-associated receptor 1 (TAAR1). Moreover, we demonstrated that activation of the BDNF-TrkB signalling is required for T₁AM action during ischemia. The protective effect of T₁AM was more evident when using EC slices from transgenic mutant human APP (mhAPP mice) that are more vulnerable to the effect of OGD. Our results confirm that the TH derivative T₁AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aβ-enriched environment.

Keywords: 3-iodothyronamine; Alzheimer's disease; Brain derived neurotrophic factor; Entorhinal cortex; Ischemia; Synaptic depression; Trace amine-associated receptor 1.