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

• Published in: Neurobiology of disease 2021-04, Vol.151, p.105271-105271, Article 105271
• Main Authors: Tozzi, Francesca, Rutigliano, Grazia, Borsò, Marco, Falcicchia, Chiara, Zucchi, Riccardo, Origlia, Nicola
• Format: Article
• Language: English
• Subjects: 3-iodothyronamine; Alzheimer's disease; Brain derived neurotrophic factor; Entorhinal cortex; Ischemia; Synaptic depression; Trace amine-associated receptor 1
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105271

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. •T1AM ameliorates ischemia-induced synaptic dysfunction in the mouse entorhinal cortex.•TAAR1 mediates T1AM protective effect on OGD-induced synaptic failure.•T1AM signalling involves BDNF and its receptor TrkB.•The protective effect of T1AM is enhanced in an AD mouse model.