The Stress-Regulated Protein M6a Is a Key Modulator for Neurite Outgrowth and Filopodium/Spine Formation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (47), p.17196-17201
• Main Authors: Julieta Alfonso, María E. Fernández, Benjamin Cooper, Flugge, Gabriele, Alberto C. Frasch
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Behavioral neuroscience; Biological Sciences; Brain; Cell Line, Tumor; Cell lines; Cell Membrane - genetics; Cell Membrane - pathology; Cell Membrane - physiology; Cells, Cultured; Chlorocebus aethiops; COS Cells; Dendrites; Dendritic Spines - physiology; Glycoproteins; Hippocampus; Hippocampus - cytology; Hippocampus - physiology; Hippocampus - physiopathology; Male; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Membranes; Mice; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurites; Neurites - physiology; Neurology; Neuronal Plasticity - genetics; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - physiology; PC12 Cells; Pseudopodia; Pseudopodia - physiology; Rats; RNA, Small Interfering - pharmacology; Small interfering RNA; Stress; Stress, Physiological - metabolism; Stress, Physiological - pathology; Stress, Physiological - physiopathology; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504262102

Neuronal remodeling is a fundamental process by which the brain responds to environmental influences, e.g., during stress. In the hippocampus, chronic stress causes retraction of dendrites in CA3 pyramidal neurons. We have recently identified the glycoprotein M6a as a stress-responsive gene in the hippocampal formation. This gene is down-regulated in the hippocampus of both socially and physically stressed animals, and this effect can be reversed by antidepressant treatment. In the present work, we analyzed the biological function of the M6a protein. Immunohistochemistry showed that the M6a protein is abundant in all hippocampal subregions, and subcellular analysis in primary hippocampal neurons revealed its presence in membrane protrusions (filopodia/spines). Transfection experiments revealed that M6a overexpression induces neurite formation and increases filopodia density in hippocampal neurons. M6a knockdown with small interference RNA methodology showed that M6a low-expressing neurons display decreased filopodia number and a lower density of synaptophysin clusters. Taken together, our findings indicate that M6a plays an important role in neurite/filopodium outgrowth and synapse formation. Therefore, reduced M6a expression might be responsible for the morphological alterations found in the hippocampus of chronically stressed animals. Potential mechanisms that might explain the biological effects of M6a are discussed.