Neuroserpin regulates the density of dendritic protrusions and dendritic spine shape in cultured hippocampal neurons

Abstract

Neuroserpin is a member of the serpin superfamily that is expressed principally in neurons of the central and peripheral nervous systems. Neuroserpin's spatial-temporal expression during development and in the adult brain suggests possible roles in synaptogenesis and synaptic plasticity. This is supported by behavioral changes in transgenic mice overexpressing neuroserpin. We have used an embryonic rat primary hippocampal neuron culture model to investigate whether neuroserpin can regulate elements of synaptic morphology that may be involved in these changes in cognitive function. Neuroserpin localized to axonal and dendritic compartments in cultured neurons and accumulated in synapsin-positive presynaptic terminals. Increased expression of neuroserpin resulted in an increase in the density of dendritic protrusions and alterations in dendritic spine shape. Our results identify neuroserpin as a new regulator of structural plasticity and suggest a cellular mechanism that may contribute to neuroserpin's effects on cognition.

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

“…Our analysis of neuroserpin-deficient mice, together with findings previously obtained with primary neurons overexpressing neuroserpin (Borges et al 2010), argue for a role of neuroserpin in regulating synaptic density and plasticity. Since synaptic perturbations may represent structural correlates of neuropsychiatric disorders (Penzes et al 2011) and dysregulated expression of neuroserpin has been found in schizophrenia (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014) we investigated neuroserpin levels in patients suffering from neuropsychiatric disorders.…”

“…Therefore, our results relating a decrease in spine-synapses to deficiency in synaptic potentiation and cognitive and social dysfunction in hippocampaldependent tasks are in line with previous findings. An influence of neuroserpin on spine morphology has already been described in primary neurons, where overexpression of neuroserpin led to a shift from mushroom-type to thin spines (Borges et al 2010). Similarly, in rat hippocampus, AAV-mediated overexpression of neuroserpin led to decreased PSD-95 expression (Tsang et al 2014), a postsynaptic scaffold protein required for synapse stabilization and modulation of synaptic plasticity (Ehrlich et al 2007;Cane et al 2014).…”

“…Reduced spine-synapse density and elevated levels of the postsynaptic scaffold protein PSD-95 in neuroserpin-deficient mice Overexpression of neuroserpin in cultured hippocampal neurons has previously been shown to regulate density and shape of dendritic spines (Borges et al 2010). To evaluate neuroserpin's role in synaptic connectivity in vivo, ultrastructural analysis was performed.…”

“…Next, since neuroserpin is transported along axons and dendrites and accumulates at presynaptic terminals (Ishigami et al 2007;Borges et al 2010), we focused on presynaptic mechanisms contributing to synaptic potentiation. To evaluate whether presynaptic function is changed in neuroserpin knockout mice, we examined paired-pulse facilitation by measuring fEPSP slopes in response to two stimuli delivered at various interstimulus intervals (Fig.…”

“…Recently, the hypothetical role of neuroserpin in synaptic formation and plasticity has been experimentally substantiated. Overexpression of neuroserpin in primary neurons leads to increased dendritic arborization and altered dendritic spine shape (Borges et al 2010), whereas in rat hippocampus neuroserpin overexpression results in reduced expression of postsynaptic density protein 95 (PSD-95) without impairment in hippocampaldependent learning and memory (Tsang et al 2014). Moreover, expression levels of N-cadherin, an adhesion protein implicated in synapse formation, are modulated by neuroserpin (Lee et al 2008).…”