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

Area of Science:

• Neuroscience
• Endocrinology
• Molecular Biology

Background:

• Thyroid hormone (TH) imbalances are linked to Alzheimer's disease (AD) and stroke risk.
• 3-iodothyronamine (T1AM), a TH metabolite, shows potential in improving learning and memory.
• T1AM can reverse beta-amyloid-induced synaptic plasticity deficits in the entorhinal cortex (EC), a region affected in AD.

Purpose of the Study:

• To investigate the neuroprotective effects of T1AM against ischemia-induced synaptic dysfunction in the EC.
• To elucidate the molecular mechanisms underlying T1AM's protective action during ischemic conditions.

Main Methods:

• Experiments were conducted on EC brain slices subjected to oxygen-glucose deprivation (OGD) to model ischemia.
• The effects of T1AM perfusion on synaptic function were assessed.
• The roles of trace amine-associated receptor 1 (TAAR1) and BDNF-TrkB signaling were investigated.
• Studies included experiments with transgenic mutant human APP (mhAPP) mice.

Main Results:

• Acute T1AM perfusion prevented ischemia-induced synaptic depression in EC slices.
• This protective effect was mediated by TAAR1 activation.
• Activation of BDNF-TrkB signaling was essential for T1AM's neuroprotective action during ischemia.
• T1AM's protective effects were more pronounced in mhAPP mice, which are more vulnerable to OGD.
• T1AM also rescued synaptic function in an environment enriched with beta-amyloid.

Conclusions:

• T1AM demonstrates significant neuroprotective capabilities against transient ischemia-induced synaptic dysfunction in the EC.
• The findings highlight T1AM as a potential therapeutic agent for conditions involving ischemic brain injury and AD-related synaptic deficits.
• The study underscores the importance of TAAR1 and BDNF-TrkB pathways in mediating T1AM's neuroprotective effects.