Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors

Yuan, Aidong; Veeranna; Sershen, Henry; Basavarajappa, Balapal S.; Smiley, John F.; Hashim, Audrey; Bleiwas, Cynthia; Berg, Martin; Guifoyle, David N.; Subbanna, Shivakumar; Darji, Sandipkumar; Kumar, Asok; Rao, Mala V.; Wilson, Donald A.; Julien, Jean-Pierre; Javitt, Daniel C.; Nixon, Ralph A.

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophreniaassociated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL−/− deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/− mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.


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February 8, 2019