👤 Natalia Abate

The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R activation promotes neurite outgrowth, enhances long-term potentiation (LTP), stimulates local protein synthesis at synapses, and regulates mitochondrial functions, and the mTOR pathway. These properties make the 5-HT7R a compelling candidate for therapeutic intervention in neurodevelopmental disorders characterized by synaptic dysfunctions. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, resulting in impairments of synaptic plasticity, dendritic spine density, protein synthesis, mitochondrial activity and mTOR signaling. Intriguingly, many of the processes altered in AS are the ones that are positively regulated by 5-HT7R activation. For instance, AS animal models exhibit reduced LTP and altered dendritic morphology and 5-HT7R stimulation enhances synaptic strength and spine formation in the brain of wild type rodents. Moreover, BDNF/TrkB function signaling is impaired and mitochondrial integrity is disrupted in AS and 5-HT7R agonists enhance the altered BDNF/TrkB signalling and restore mitochondrial dysfunctions in Rett syndrome (RTT) mice model. Interestingly, recent evidence demonstrates that pharmacological activation of 5-HT7Rs increases synaptic protein synthesis, restores LTP, enhances dendritic spine density, and improves cognitive function in an AS mouse model. These encouraging results open the way to future studies using neurons and brain organoids generated from iPSCs obtained from AS patients, which represent novel tools in preclinical research. Overall, 5-HT7R stimulation, by counteracting the molecular alterations associated with the loss of UBE3A, may represent a novel approach to restore neural function in the mature brain, leading to translational applications in AS patients, and possibly also in other synaptopathies. Clinical trial number: not applicable. Show less

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca Show less