T 1 AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex

Francesca Tozzi, Grazia Rutigliano, Marco Borsò, Chiara Falcicchia, Riccardo Zucchi, Nicola Origlia
Neurobiology of Disease 2021 January 19, : 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 (T1 AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T1 AM 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 T1 AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T1 AM (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 T1 AM action during ischemia. The protective effect of T1 AM 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 T1 AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aβ-enriched environment.

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