Endocrine Abstracts

Abnormalities in thyroid hormone (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 modulate the nervous and the vascular systems. In the present work, we studied the effect of T1AM on ischemia-induced synaptic dysfunction in the entorhinal cortex (EC), a brain region crucially involved in learning and memory and early affected during AD. Moreover, we investigated the role of the trace amine-associated receptor 1 (TAAR1) and its signalling in T1AM-mediated neuroprotection. Field excitatory post-synaptic potentials (fEPSPs) were recorded in EC horizontal slices obtained from WT mice (C57bl). Slices were exposed to an oxygen-glucose deprivation (OGD) protocol for 10 min and then recorded for 50 min after reperfusion. Drugs were perfused to slices for 10 min during the application of OGD. A long-lasting synaptic depression was induced by OGD in C57bl slices (mean fEPSP amplitude in the last 10 min of recording was of 77 ± 4% of baseline, n = 13 slices, 6 mice). However, T1AM (5 µM) perfusion was capable of preventing the long-lasting synaptic depression after OGD (mean fEPSP amplitude 96 ± 4% of baseline, n = 10 slices, 6 mice). A similar protective effect was achieved by perfusion with RO5166017 (250 nM), a specific agonist of TAAR1(mean fEPSP amplitude 99 ± 6% of baseline, n = 6 slices, 4 mice), while T1AM protective effect was abolished in the presence of EPPTB (5 nM), a selective TAAR1 antagonist (mean fEPSP amplitude was of 81 ± 4% of baseline, n = 9 slices, 4 mice). Moreover, T1AM failed to protect against ischemia in the presence of a TRKB IgG capable of blocking BDNF (1 µg/ml) (mean fEPSP amplitude 55 ± 4% of baseline, n = 12 slices, 4 mice), or in the presence of an antibody against TRKB (1 µg/ml) (mean fEPSP amplitude 63 ± 5% of baseline, n = 7, 3 mice), or with a selective PI3K inhibitor, LY294002 (10 nM) (mean fEPSP amplitude 58 ± 5%, n = 7 slices, 3 mice), suggesting that BDNF signalling may contribute T1AM-mediated neuroprotection. Interestingly, the putative T1AM precursor, triiodothyronine (T3), and its oxidative metabolite, the 3-iodothyroacetic acid (TA1), didn’t possess the same neuroprotective ability. Therefore, our results demonstrate that T1AM can ameliorate ischemia-induced synaptic dysfunction in the mouse EC and suggest that T1AM neuroprotection is mediated by TAAR1 signalling.