Spinophilin regulates the formation and function of dendritic spines

Abstract

Spinophilin, a protein that interacts with actin and protein phosphatase-1, is highly enriched in dendritic spines. Here, through the use of spinophilin knockout mice, we provide evidence that spinophilin modulates both glutamatergic synaptic transmission and dendritic morphology. The ability of protein phosphatase-1 to regulate the activity of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors was reduced in spinophilin knockout mice. Consistent with altered glutamatergic transmission, spinophilin-deficient mice showed reduced long-term depression and exhibited resistance to kainate-induced seizures and neuronal apoptosis. In addition, deletion of the spinophilin gene caused a marked increase in spine density during development in vivo as well as altered filopodial formation in cultured neurons. In conclusion, spinophilin appears to be required for the regulation of the properties of dendritic spines. D endritic spines are specialized protrusions from dendritic shafts that receive the vast majority of excitatory input in the central nervous system (1). Dynamic changes in the number, size, and shape of dendritic spines have been associated with learning (2, 3), electrophysiological (4-6), developmental (7,8), and hormonal changes (9, 10). It is increasingly evident that alterations in synaptic activity can cause morphological changes of dendritic spines (2,(11)(12)(13)(14): high-intensity stimulation of CA1 neurons induces rapid formation of spine-like protrusions (or filopodia) (12), and decreased synaptic activity results in loss of dendritic spines (14). Conversely, morphological changes in dendritic spines have profound effects on their electrical and biochemical properties (15-17), thereby regulating the efficacy of synaptic transmission (13,18,19). However, with the exception of evidence that localization of glutamate receptors is altered with neuronal activity (20, 21), little is known about the molecular mechanisms underlying the linkage between synaptic activity and the dynamic morphological changes of dendritic spines.Spinophilin, also called neurabin II (22), interacts with several proteins that are highly enriched in spines (22,23). One of them, actin, is important for the formation, maintenance, and morphology of spines (18). In vitro, spinophilin bundles actin filaments (22), suggesting its possible role as one organizer of the actin-based cytoskeleton in dendritic spines. Another binding partner of spinophilin that is enriched in dendritic spines is protein phosphatase-1 (PP-1) (23, 24). There is evidence that PP-1 modulates the activity of a variety of ion channels, including glutamate receptors (25-28). These properties of spinophilin make it an attractive candidate for regulating the dynamic morphological and functional changes that occur in dendritic spines. To investigate the possible role of spinophilin in spine formation and function, we used gene-targeting methods to generate mice that lack the expression of spinophilin. MethodsGeneration ...

Localization and Regulation of the Tissue Plasminogen Activator–Plasmin System in the Hippocampus

“…This is exemplified by experiments showing that loss of tPA or plasminogen conferred neuronal protection after excitotoxic injury (Tsirka et al, 1995) and stroke (Wang et al, 1998). Several other proteins have been identified whose absence confers resistance to excitotoxin-induced neuronal degeneration: jnk3 (Yang et al, 1997), preprotachykinin A (Liu et al, 1999), glutathione peroxidase (Jiang et al, 2000), and spinophilin (Feng et al, 2000). It is not clear that all of these players lie in the same pathway for neurodegeneration, but loss of any of these components provides some degree of neuroprotection.…”

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

“…Reduced mRNA expression of cell division cycle 42, which promotes dendritic spine outgrowth (Irie and Yamaguchi, 2002), and Kalirin 7, which is necessary for both spine outgrowth and mediates LTP-induced spine structural plasticity (Penzes et al, 2001), was found in PFC, and correlated with reductions in spine density (Hill et al, 2006). Of interest, spinophilin has been recently shown to be a mediator of LTD-, but not LTPinduced structural plasticity (Feng et al, 2000). These effects are mediated via recruitment of the Rho guanine exchange factor, Lfc (Lbc (lymphoid blast crisis)'s first cousin), into spines (Ryan et al, 2005), and via targeting of protein phosphatase 1 to glutamate receptors within spines (Feng et al, 2000) and to actin (Fernandez et al, 1990).…”

“…Of interest, spinophilin has been recently shown to be a mediator of LTD-, but not LTPinduced structural plasticity (Feng et al, 2000). These effects are mediated via recruitment of the Rho guanine exchange factor, Lfc (Lbc (lymphoid blast crisis)'s first cousin), into spines (Ryan et al, 2005), and via targeting of protein phosphatase 1 to glutamate receptors within spines (Feng et al, 2000) and to actin (Fernandez et al, 1990). As reviewed above, there is evidence to suggest spinophilin expression is increased or unchanged in cortical extracts of subjects with schizophrenia.…”

“…An important consideration is whether the reduction in SP-IR puncta density in our subjects with schizophrenia resulted from a reduced density of dendritic spines, or a reduced detectability of spinophilin protein, as mice lacking spinophilin demonstrate increased or normal spine density (Feng et al, 2000). We used a stereologic approach to count individual SP-IR puncta.…”

Structural Basis for Spinophilin−Neurabin Receptor Interaction

“…Neurabin (1) and spinophilin (2)(3)(4) are neuronal scaffolding proteins that play important roles in synaptic transmission and synaptic plasticity (5,6). Neurabin and spinophilin are highly enriched in dendritic spines, the site of excitatory neurotransmission.…”