Neurofilament subunits are integral components of synapses and modulate neurotransmission and behavior in vivo

• Published in: Molecular psychiatry Vol. 20; no. 8; pp. 986 - 994
• Main Authors: Yuan, A, Sershen, H, Veeranna, Basavarajappa, B S, Kumar, A, Hashim, A, Berg, M, Lee, J-H, Sato, Y, Rao, M V, Mohan, P S, Dyakin, V, Julien, J-P, Lee, V M-Y, Nixon, R A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2015; Nature Publishing Group
• Subjects: 14; 631/378; 64; 64/110; 64/60; 82; 82/16; 82/29; 82/51; Animals; Axons; Axons - drug effects; Axons - physiology; Behavioral Sciences; Biological Psychology; Brain - drug effects; Brain - physiology; Brain research; Cocaine; Cocaine - pharmacology; Cytoplasmic filaments; Dementia; Dopamine; Dopamine D1 receptors; Dopamine Uptake Inhibitors - pharmacology; Endosomes; Health aspects; Hippocampus; Kinases; Long-term potentiation; Long-Term Potentiation - physiology; Medicine; Medicine & Public Health; Mice, Knockout; Motor Activity - drug effects; Motor Activity - physiology; Neural transmission; Neurofilament Proteins - genetics; Neurofilament Proteins - metabolism; Neurosciences; Neurotransmission; original-article; Pharmacotherapy; Phosphorylation; Proteins; Psychiatry; Receptors, Dopamine D1 - metabolism; Roles; Stoichiometry; Synapses; Synapses - drug effects; Synapses - physiology; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; New York; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.45

Synaptic roles for neurofilament (NF) proteins have rarely been considered. Here, we establish all four NF subunits as integral resident proteins of synapses. Compared with the population in axons, NF subunits isolated from synapses have distinctive stoichiometry and phosphorylation state, and respond differently to perturbations
in vivo
. Completely eliminating NF proteins from brain by genetically deleting three subunits (α-internexin, NFH and NFL) markedly depresses hippocampal long-term potentiation induction without detectably altering synapse morphology. Deletion of NFM in mice, but not the deletion of any other NF subunit, amplifies dopamine D1-receptor-mediated motor responses to cocaine while redistributing postsynaptic D1-receptors from endosomes to plasma membrane, consistent with a specific modulatory role of NFM in D1-receptor recycling. These results identify a distinct pool of synaptic NF subunits and establish their key role in neurotransmission
in vivo
, suggesting potential novel influences of NF proteins in psychiatric as well as neurological states.