Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons

Abstract

Synaptophysin is an abundant synaptic vesicle protein without a definite synaptic function. Here, we examined a role for synaptophysin in synapse formation in mixed genotype micro-island cultures of wild-type and synaptophysin-mutant hippocampal neurons. We show that synaptophysin-mutant synapses are poor donors of presynaptic terminals in the presence of competing wild-type inputs. In homogenotypic cultures, however, mutant neurons display no apparent deficits in synapse formation compared with wild-type neurons. The reduced extent of synaptophysin-mutant synapse formation relative to wild-type synapses in mixed genotype cultures is attenuated by blockers of synaptic transmission. Our findings indicate that synaptophysin plays a previously unsuspected role in regulating activity-dependent synapse formation.culture ͉ activity ͉ synaptic competition T he mechanism underlying the formation of functional synaptic circuits is one of the central problems of neurobiology that remains to be resolved. In the prevailing view, growing axons are guided to their targets and undergo synaptogenesis by predominantly activity-independent processes. Subsequently, the initial rough connections are refined by activity-dependent synapse remodeling, in which active synapses are preferentially stabilized at the expense of less active synapses to generate an optimal synaptic circuit supporting nervous system function (1-3). The molecular mechanisms of synaptogenesis and synapse remodeling are best understood at the neuromuscular junction, where some of the key molecular players have been identified (4). In central neurons, however, the mechanisms that drive the formation of functional synaptic circuits remain largely unknown.Synaptophysin I (syp) is a synaptic vesicle membrane protein that is ubiquitously expressed throughout the brain (5, 6). Despite its abundance, analysis of syp interactions with other synaptic vesicle proteins and presynaptic molecules has not revealed a clear function. A possible role for syp in regulating synaptic vesicle cycling has been suggested by the findings that antibodies to syp reduce neurotransmitter release in Xenopus neuromuscular synapses (7), and that peptides which interfere with syp binding to dynamin, a component of endocytic machinery, block endocytosis at squid giant synapse (8). Mice carrying a targeted deletion of the syp gene, however, do not display any obvious phenotype to support these proposals (9). The anatomical structure and protein composition of the brain seem normal, and the properties of baseline synaptic transmission and shortand long-term synaptic plasticity also are unchanged compared with wild-type mice. These results have suggested that syp function is either redundant or compensated for by other proteins (9). It also is possible that syp plays a subtle, nonessential regulatory role in some aspect of synapse function that is not apparent when comparing the differences between wild-type and mutant animals.Here, we investigate a role of syp in synapse formation in the presence...

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

“…Various proteins like synaptophysin, N-methyl-Daspartate receptor subunit 1, PSD95, and calcium/ calmodulin-dependent protein kinase II alpha, which are involved in neurotransmission at the synapses, are associated with synaptic plasticity (Yang et al 2014). Synaptophysin is a synaptic vesicle glycoprotein essential for synapse formation in the culture hippocampal neurons (Tarsa and Goda 2002) and is also associated well with differences in cognitive performance in mice (Mulder et al 2004). The loss of pre-synaptic vesicle protein in hippocampus correlates with the cognitive decline in Alzheimer's disease (Reddy et al 2005).…”

Synapse-Specific Regulation of AMPA Receptor Subunit Composition by Activity

“…In this way, we could examine the effect of inhibition at a definable set of synapses in an otherwise normally active culture. Although synaptophysin is not an essential protein, overexpression of SYNYFP may itself have an effect on synapses (Tarsa and Goda, 2002), so we compared the effects of expression of TNTCFP plus SYNYFP with expression of CFP plus SYNYFP Figure 1. Selective losses of VAMP2 and FM dye uptake from TNTCFP-expressing synapses.…”

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

“…MAP-2 is a dendritic protein responsible for the assembly of the microtubules in the dendrites and aids in dendritic plasticity (Harada et al 2002). SYN is a presynaptic vesicle protein located in axons associated with synaptic vesicles and is responsible for formation of synapses (Tarsa and Goda 2002). SYN levels also positively correlate with cognitive function in rodents (Dawson et al 1999;Mulder et al 2004).…”