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

Abstract

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 schizophrenia-associated 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.

Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease

“…Golgi staining for spine density and morphology Golgi staining was performed using the FD Rapid Golgi Stain kit (FD NeuroTechnologies) as previously described (Yuan et al, 2018). Spines were sampled on 3-4 dendrites on each of 3 cells per area, per animal, in the dorsal hippocampus.…”

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

“…Neuro lament disorganization can contribute to neuronal dysfunction and death (34,35). Reduced expression of Ne or Nefm proteins has been shown to cause defect in synaptic function with ensuing behavioral impairment (36,37). Previous reports showed that TDP-43 can bind and stabilize neuro lament mRNAs (2,38).…”

Intermediate filaments in developing neurons: Beyond structure

“…For example, NF-L binds to the cytoplasmic tail of the GluN1/NR1 subunit of the NMDA receptor and to protein phosphatase 1 (PP1) (Ehlers, Fung, O'Brien, & Huganir, 1998;Ratnam & Teichberg, 2005;Terry-Lorenzo et al, 2000). Indeed, NF-L knockout neurons exhibit reduced spine density and length with schizophrenialike behavioral defects (Yuan et al, 2018). INA/NF-I interacts with the PP1 scaffold spinophilin in an age-dependent manner, that is, more INA/NF-I co-IPs with spinophilin in adult compared to postnatal brain (Baucum et al, 2010;Baucum, Strack, & Colbran, 2012).…”