The stress-related protein M6A is a key regulator for neurite outgrowth and filopodium/ spine formation

JULIETA ALFONSO; M E FERNADEZ; B COOPER; LUCIANA R FRICK; DAFNE MAGALÍ SILBERMAN; MARÍA LAURA PALUMBO; ANA MARÍA GENARO; G. FLUGGE; ALBERTO CARLOS FRASCH

Washington USA

Congreso; XXXV Anual Meeting of the Society for Neuroscience (SFN); 2005

Society for Neurosicence (SFN)

Chronic stress has severe effects on hippocampal structure and function, but the molecular mechanisms responsible for these alterations are largely unknown. Both chronic psychosocial stress in male tree shrews and repeated restraint stress in rodents show similar hippocampal remodeling which can be reversed by antidepressant treatment. Using subtractive libraries, we have previously identified the glycoprotein M6a as a gene regulated by stress/antidepressant treatment in the hippocampus of stressed tree shrews. We now show that mice exposed to chronic restraint stress also display a reduction in hippocampal transcript levels for this gene and that this effect is counteracted by tianeptine treatment. Therefore, the conserved regulation of M6a in different species, stress models and antidepressant drugs highlights the biological relevance of this gene. Next, we investigated the biological function of the M6a protein. Immunohistochemistry assays showed that M6a protein is abundant in all hippocampal subregions and subcellular analysis in primary hippocampal neurons showed the presence of M6a in filopodia/spines. Transfection experiments revealed that M6a overexpression induces neurite formation and increases filopodium/spine density in hippocampal neurons. M6a knock down with siRNA methodology showed that M6a low expressing neurons display decreased filopodium/spine number and a lower density of synaptophysin clusters. Our findings indicate that M6a plays an important role in neurite/filopodium outgrowth and synapse formation, suggesting that reduced M6a expression might therefore contribute to the morphological alterations found in the hippocampus of chronically stressed animals.