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• W2017684482 abstract "Synapses in the brain must maintain a balance between learning-related plasticity and the stability necessary for reliable function. In this issue of Neuron, Calabrese and Halpain describe cell-transfection experiments implicating MARCKS, a protein that binds to both the cell surface and actin cytoskeleton, in the maintenance of dendritic spines. Synapses in the brain must maintain a balance between learning-related plasticity and the stability necessary for reliable function. In this issue of Neuron, Calabrese and Halpain describe cell-transfection experiments implicating MARCKS, a protein that binds to both the cell surface and actin cytoskeleton, in the maintenance of dendritic spines. Recent live cell-imaging studies have identified dendritic spines as major sites of morphological plasticity in brain circuits. In the cerebral cortex of the adult mouse, spines on pyramidal neurons can be roughly divided into two plasticity categories, those that are maintained over long periods, perhaps extending to the entire lifetime of an animal, and a small yet significant fraction that turn over within a few days (Holtmaat et al., 2005Holtmaat A.J. Trachtenberg J.T. Wilbrecht L. Shepherd G.M. Zhang X. Knott G.W. Svoboda K. Neuron. 2005; 45: 279-291Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar). In vitro imaging studies indicate that spine plasticity depends on dynamic actin filaments concentrated in the spine head (Fischer et al., 1998Fischer M. Kaech S. Knutti D. Matus A. Neuron. 1998; 20: 847-854Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar, Korkotian and Segal, 2001Korkotian E. Segal M. Neuron. 2001; 30: 751-758Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), so the search is on for modulators of actin dynamics that may account for these variations in spine stability in the intact brain. Calabrese and Halpain (Calabrese and Halpain, 2005Calabrese B. Halpain S. Neuron. 2005; 48 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) now present data implicating MARCKS (myristoylated, alanine-rich C kinase substrate), a lipid binding protein that influences cell morphology and motility, as a key player in the mechanism that regulates spine maintenance. MARCKS modulates signaling from the surface to the actin cytoskeleton by regulating the availability of the membrane-associated phospholipid PIP2 (Janmey and Lindberg, 2004Janmey P.A. Lindberg U. Nat. Rev. Mol. Cell Biol. 2004; 5: 658-666Crossref PubMed Scopus (184) Google Scholar, Laux et al., 2000Laux T. Fukami K. Thelen M. Golub T. Frey D. Caroni P. J. Cell Biol. 2000; 149: 1455-1472Crossref PubMed Scopus (514) Google Scholar). In the brain, MARCKS is a major target of activity-dependent phosphorylation by protein kinase C (PKC), and previous studies have suggested that this function is important for memory and synaptic plasticity. For example, visual imprinting in young chicks produced selective phosphorylation of MARCKS in the hyperstriatum ventrale, an area thought to serve as a storage site for recognition memory (Sheu et al., 1993Sheu F.S. McCabe B.J. Horn G. Routtenberg A. Proc. Natl. Acad. Sci. USA. 1993; 90: 2705-2709Crossref PubMed Scopus (86) Google Scholar). Both down- and upregulation of MARCKS can produced learning deficits so that both heterozygous knockout mice with a 50% reduction in MARCKS expression and transgenic mice overexpressing exogenous MARCKS show significant impairments of spatial learning (McNamara et al., 2005McNamara R.K. Hussain R.J. Simon E.J. Stumpo D.J. Blackshear P.J. Abel T. Lenox R.H. Hippocampus. 2005; 15: 675-683Crossref PubMed Scopus (28) Google Scholar). These observations support a role for MARCKS in learning and memory, but there has been little evidence to explain its function at the cellular level. Interaction of the MARCKS protein with the cell surface is controlled by two sites in the molecule, a hydrophobic myristoyl residue at the N terminus and an effector domain (ED) containing a short stretch of basic amino acids that binds to acidic phospholipids on the cell membrane. Phosphorylation by PKC of four serine residues within the effector domain redistributes MARCKS from the cell surface to the cytoplasm and also regulates its binding to actin filaments and calmodulin in a mutually exclusive fashion. Calabrese and Halpain have analyzed the influence of these interactions on spine stability by transfecting cultured hippocampal neurons with a set of mutant MARCKS constructs. However, first they examined the effects of simply ablating MARCKS expression by an RNA interference approach, an experiment that had not been done previously because homozygous MARCKS knockout mice are not viable. In neurons in which MARCKS expression was almost entirely suppressed, there was a dramatic destabilization of spine morphology with spine numbers as well as the length and width of those remaining all greatly reduced. Interestingly, there was no apparent effect on the dendrites themselves, suggesting a specific role for MARCKS in regulating spine morphology. The converse experiment of overexpressing wild-type MARCKS also reduced the density of spines on dendrites of transfected cells by approximately half, and the remaining protrusions were narrower and strikingly longer than those of control cells. The similar effects of both reducing and increasing MARCKS levels indicate that balanced expression is necessary for spine maintenance. A similar “balance” appears to operate in relationship to phosphorylation of the effector domain. Transfecting cells with a construct in which the four phosphorylated serines in the effector domain were replaced by alanines so that they could not be phosphorylated produced effects similar to the wild-type protein, probably reflecting the fact that both bind strongly to the cell membrane when overexpressed. The “opposite” modification of substituting the effector domain serines by aspartic acid residues to mimic phosphorylation appropriately reduces binding to the plasma membrane. Cells transfected with this pseudophosphorylated protein also had significantly fewer spines, but, interestingly, those remaining showed overall shrinkage, being both shorter and narrower than control spines. Calabrese and Halpain also examined a point mutation that blocks myristoylation of the N terminus, which also produced abnormally longer and thinner spines. However, it is the effector domain phosphorylation mutants that provide the most interesting insights into MARCKS function. Double-labeling experiments with antibodies against the presynaptic marker synaptophysin showed that cells transfected with both pseudophosphorylated and nonphosphorylatable MARCKS constructs were contacted by the same numbers of presynaptic terminals as control cells. These were distributed as multiple contacts on reduced number of remaining spines. Even more surprisingly, electrophysiological recordings showed no significant changes in either the frequency or amplitude of miniature excitatory postsynaptic currents, indicating that compensatory rearrangement of connections had preserved synaptic function. Unsurprisingly, given the actin binding and PIP2-modulating functions of the effector domain, the changes in spine morphology produced by transfecting MARCKS phosphorylation mutants were accompanied by reorganization of the actin cytoskeleton. The effects were opposite for pseudophosphorylated MARCKS, which enhanced the clustering of actin at the tips of spines, and the nonphosphorylatable mutant, which instead induced dispersal of actin clusters away from the spine tip. These differences were also reflected in their effects on actin filament dynamics, which produce rapid changes in the shapes of spine heads (Dunaevsky et al., 1999Dunaevsky A. Tashiro A. Majewska A. Mason C. Yuste R. Proc. Natl. Acad. Sci. USA. 1999; 96: 13438-13443Crossref PubMed Scopus (367) Google Scholar, Fischer et al., 1998Fischer M. Kaech S. Knutti D. Matus A. Neuron. 1998; 20: 847-854Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar). This motile activity was significantly reduced in cells expressing pseudophosphorylated MARCKS, whereas the nonphosphorylatable mutant had no detectable effect. Actin-dependent spine motility is downregulated by glutamate receptor activation (Fischer et al., 2000Fischer M. Kaech S. Wagner U. Brinkhaus H. Matus A. Nat. Neurosci. 2000; 3: 887-894Crossref PubMed Scopus (400) Google Scholar, Korkotian and Segal, 2001Korkotian E. Segal M. Neuron. 2001; 30: 751-758Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Richards et al., 2004Richards D.A. De Paola V. Caroni P. Gahwiler B.H. McKinney R.A. J. Physiol. 2004; 558: 503-512Crossref PubMed Scopus (46) Google Scholar), suggesting that MARCKS phosphorylation may represent one of the pathways involved in receptor-dependent regulation of spine plasticity. What, then, are the signaling events involved in these effects of MARCKS phosphorylation? To answer this question Calabrese and Halpain examined the effects of treating cultured cells with a phorbol ester, which activates neuronal PKC, and found the same loss of spines and shrinkage of those remaining that they had earlier produced by transfecting cells with pseudophosphorylated MARCKS. Significantly, transfecting cells with the nonphophorylatable form of MARCKS could antagonize these effects of phorbol ester. Altogether these observations are consistent with a scheme in which activity-induced phosphorylation of MARCKS by PKC inhibits its interaction with cell membrane, unmasking PIP2 clusters associated with lipid rafts, which then signal to the actin cytoskeleton to alter spine motility and morphology. This interpretation is supported by experiments in which direct manipulation of lipid rafts was shown to strongly affect the maintenance of spine morphology (Hering et al., 2003Hering H. Lin C.C. Sheng M. J. Neurosci. 2003; 23: 3262-3271Crossref PubMed Google Scholar). However, phosphorylation of the effector domain also influences binding to calcium/calmodulin, suggesting that MARCKS has additional effects on neuronal function beyond those addressed by these experiments. Ultimately, these experiments should help untangle some of the complexities of MARCKS function and its relationship to PKC-dependent plasticity mechanisms. This should not only further our understanding of the cellular mechanisms involved in learning and memory but may also shed some light on evidence for abnormal MARCKS expression in patients with bipolar disorders and suicide victims (McNamara et al., 2005McNamara R.K. Hussain R.J. Simon E.J. Stumpo D.J. Blackshear P.J. Abel T. Lenox R.H. Hippocampus. 2005; 15: 675-683Crossref PubMed Scopus (28) Google Scholar)." @default.
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• W2017684482 title "MARCKS for Maintenance in Dendritic Spines" @default.
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