Both Pre- and Postsynaptic Activity of Nsf Prevents Degeneration of Hair-Cell Synapses

Abstract

Vesicle fusion contributes to the maintenance of synapses in the nervous system by mediating synaptic transmission, release of neurotrophic factors, and trafficking of membrane receptors. N-ethylmaleimide-sensitive factor (NSF) is indispensible for dissociation of the SNARE-complex following vesicle fusion. Although NSF function has been characterized extensively in vitro, the in vivo role of NSF in vertebrate synaptogenesis is relatively unexplored. Zebrafish possess two nsf genes, nsf and nsfb. Here, we examine the function of either Nsf or Nsfb in the pre- and postsynaptic cells of the zebrafish lateral line organ and demonstrate that Nsf, but not Nsfb, is required for maintenance of afferent synapses in hair cells. In addition to peripheral defects in nsf mutants, neurodegeneration of glutamatergic synapses in the central nervous system also occurs in the absence of Nsf function. Expression of an nsf transgene in a null background indicates that stabilization of synapses requires Nsf function in both hair cells and afferent neurons. To identify potential targets of Nsf-mediated fusion, we examined the expression of genes implicated in stabilizing synapses and found that transcripts for multiple genes including brain-derived neurotrophic factor (bdnf) were significantly reduced in nsf mutants. With regard to trafficking of BDNF, we observed a striking accumulation of BDNF in the neurites of nsf mutant afferent neurons. In addition, injection of recombinant BDNF protein partially rescued the degeneration of afferent synapses in nsf mutants. These results establish a role for Nsf in the maintenance of synaptic contacts between hair cells and afferent neurons, mediated in part via the secretion of trophic signaling factors.

Ribbon synapses in zebrafish hair cells

“…Both TrkB and BDNF are expressed in zebrafish hair cells and afferent neurons of the lateral line organ (Germanà et al, 2010). Secretion of BDNF requires the activity of N-ethylmaleimide sensitive factor (Nsf) in afferent neurons (Mo and Nicolson, 2011). Nsf also plays a role in hair cells, likely mediating the secretion of BDNF or other neurotrophic factors that act on afferent fibers to maintain synaptic contacts.…”

“…Nsf also plays a role in hair cells, likely mediating the secretion of BDNF or other neurotrophic factors that act on afferent fibers to maintain synaptic contacts. If Nsf is absent, then afferent synaptic contacts are lost during development (Mo and Nicolson, 2011). The nsf mutant phenotype can be partially rescued by injection of BDNF (Mo and Nicolson, 2011).…”

“…If Nsf is absent, then afferent synaptic contacts are lost during development (Mo and Nicolson, 2011). The nsf mutant phenotype can be partially rescued by injection of BDNF (Mo and Nicolson, 2011). In a similar context, reintroduction of BDNF in Pou4f3−/− mutant mice that lack hair cells caused robust sprouting of nerve fibers and better survival of afferent neurons (Fukui et al, 2012).…”

Zebrafish larvae evade predators by sensing water flow

“…Furthermore, no other species offers a greater potential for understanding the functioning of the lateral line system (e.g. Kohashi and Oda, 2008;Nagiel et al, 2009;Nuñez et al, 2009;Mo and Nicolson, 2011;Trapani and Nicolson, 2011) and the startle response (e.g. Bhatt et al, 2007;Issa et al, 2011;Nikolaou and Meyer, 2012;Liu et al, 2012) across levels of organization.…”

L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression

“…On the one side, BDNF plays a crucial role to upgrade complexity of the inner hair cell (IHC) synapse, including maintenance of mature IHC number of synaptic ribbons, electron-dense presynaptic specializations that tether synaptic vesicles for exocytosis at the active zone (Fuchs, 2005; Moser et al, 2006; Schmitz, 2009) in mice (Zuccotti et al, 2012) and zebrafish (Mo and Nicolson, 2011). On the other side, BDNF is harmful when acoustic overstimulation damages the mature system (Zuccotti et al, 2012).…”