Specialized roles of neurofilament proteins in synapses: Relevance to neuropsychiatric disorders

Abstract

Neurofilaments are uniquely complex among classes of intermediate filaments in being composed of four subunits (NFL, NFM, NFH and alpha-internexin in the CNS) that differ in structure, regulation, and function. Although neurofilaments have been traditionally viewed as axonal structural components, recent evidence has revealed that distinctive assemblies of neurofilament subunits are integral components of synapses, especially at postsynaptic sites. Within the synaptic compartment, the individual subunits differentially modulate neurotransmission and behavior through interactions with specific neurotransmitter receptors. These newly uncovered functions suggest that alterations of neurofilament proteins not only underlie axonopathy in various neurological disorders but also may play vital roles in cognition and neuropsychiatric diseases. Here, we review evidence that synaptic neurofilament proteins are a sizable population in the CNS and we advance the concept that changes in the levels or post-translational modification of individual NF subunits contribute to synaptic and behavioral dysfunction in certain neuropsychiatric conditions.

Keywords: Dendritic spine; Neurofilament subunit; Neuropsychiatric disease; Synapse.

Figure 1. Functional NF subunit assemblies in synapses

Left panel: Immunogold labeled antibodies against the NFM subunit decorating synaptic structures in a linear pattern (immunogold particles outlined in blue) suggesting the presence of short NFs and protofilament /protofibril or unit length filament assemblies. In the upper inset, a filament within a postsynaptic bouton is decorated by immunogold antibodies to both NFL (large gold dots) and NFH (small gold dots). Morphometric analysis indicates a higher density of immunogold labeling in postsynaptic boutons than in preterminal dendrites or presynaptic terminals (graph inset). Middle panel: Ultrastructural image of a human synapse depicts membranous vesicles, many of which appear to be associated with a loose network of short 10nm filaments in the post-synaptic region. Right panel: Evidence supports a biological mechanism whereby D1 dopamine receptors internalized on endosomes from the postsynaptic surface (red asterisks) dock on synaptic NF subunit assemblies (outlined in blue) where they are readily available to recycle on endosomes to the surface in response to ligand stimulation (adapted from Yuan et al. Mol Psychiatry 2015; 20:915 with permission).

Figure 2. Model of D1R–containing endosomes anchored on NFM-containing cytoskeletal assemblies

Based on collective findings on NF scaffolding functions and our D1R data on NF subunit null mice, we propose a model by which NFM acts in synaptic terminals to anchor D1R–containing endosomes formed after agonist-induced internalization of membrane D1R. Retention of D1R in a readily available internal pool within the synapse would favor desensitization to D1R stimulation: in the absence of NFM, the greater recycling back to the plasma membrane surface would favor hypersensitivity to D1R agonists, as observed in our in vivo studies (adapted from Yuan et al. Mol Psychiatry 2016; 20:986–994 with permission).