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SfN 2010—Curbing Excitation: Dendritic Spines in Mental Disorders

The Society for Neuroscience hosted more than 30,000 researchers at Neuroscience 2010 in San Diego, 13-17 November 2010. Here, we are fortunate to receive a meeting update from Nao J. Gamo, a graduate student at Yale University, New Haven, Connecticut.

3 December 2010. A mini-symposium on "Dendritic spine dysfunction in mental disorders" was held during the annual Society for Neuroscience meeting on 15 November 2010. Peter Penzes from Northwestern University Feinberg School of Medicine, Chicago, Illinois, and David Lewis from the University of Pittsburgh, Pennsylvania, chaired the session, which consisted of six brief presentations that discussed the dynamics of dendritic spines in the context of psychiatric disorders, in particular, with focus on schizophrenia and autism spectrum disorders (ASD). Dendritic spines form most of the excitatory synapses in the brain, and their structure is dynamically regulated in response to the environment, such as during stress and learning. As the morphology of spines and many spine-regulatory proteins are altered in an array of diseases, the findings discussed in this session allow better understanding of psychiatric disorders and have the potential to create improved treatments.

The first presentation was by Amanda J. Law from the National Institute of Mental Health, Bethesda, Maryland, and was titled, “Transgenic expression of Neuregulin 1, type IV regulates synaptic maturation in-vitro and impairs cortical function in mice.” Law discussed the role of a novel isoform of neuregulin-1 (NRG1)—type IV—in regulating dendritic spines at the cellular, physiological, and behavioral levels.

The NRG1 gene has been implicated widely in schizophrenia, and encodes for over 30 proteins that are involved in development and plasticity. The NRG1 receptor, ErbB4, has itself been implicated in schizophrenia, and has been shown to control glutamatergic synapse maturation and plasticity. NRG1 type IV is a brain-specific protein which is differentially expressed in the fetal and adult brains (see SRF related news story).

Law discussed findings showing that patients and control subjects carrying a genetic variation associated with schizophrenia were found to have increased mRNA expression of the type IV isoform (see SRF related news story). This upregulation likely occurred through modulation of its promoter activity and transcriptional regulation (Tan et al., 2007).

More recent experimental findings suggest that NRG1 type IV affects synaptic function at dendritic spines, which when impaired might lead to cognitive dysfunction observed in schizophrenia. Overexpression of the type IV isoform in primary hippocampal neurons was found to alter dendritic spine maturation in vitro. At the physiological level, overexpression disrupted the excitatory glutamatergic inputs to layer V pyramidal cells in the medial prefrontal cortex (PFC), and increased the firing frequency in interneurons. However, there were no changes in the formation and maintenance of glutamatergic synapses in the pyramidal cells. Consistent with these findings, transgenic mice with overexpression of NRG1 type IV in the PFC and hippocampus showed impaired object recognition memory and abnormal prepulse inhibition, a measure of pre-attentive function. These animals were otherwise healthy and showed generally normal behavior, including normal fear conditioning.

In the second presentation, David Lewis discussed the “Molecular mechanisms of lamina-specific dendritic spine alterations in schizophrenia.” Cognitive deficits associated with the dorsolateral PFC (DLPFC) are a core feature of schizophrenia. For example, schizophrenic subjects show impaired activation of the DLPFC during a working memory task, as well as impaired γ oscillations in this region during a cognitive control task.

Lewis first presented evidence to suggest that schizophrenic subjects had less excitatory synapses in deep layer III of the DLPFC relative to control subjects. Schizophrenic patients showed reduced spine density and somal volume in pyramidal cells in layer III DLPFC relative to control subjects, while the spine density in superficial layer III and layers V and VI of DLPFC and in the primary visual cortex did not differ between groups (reviewed in Lewis et al., 2003). Changes in this region would be functionally significant, as layer III pyramidal cells in the DLPFC are involved in corticocortical and thalamacortical connectivity. In fact, they are critical for γ-band oscillations and working memory, as described by Robert Desimone, and are involved in the recurrent circuits that maintain working memory, as described by Patricia Goldman-Rakic.

Lewis then discussed the possible molecular mechanisms underlying these structural changes in dendritic spines. Several interacting proteins that regulate spine dynamics have been identified, such as Cdc42, Rac1, RhoA, Duo (human orthologue of the murine Kalirin-7), and drebrin. In particular, the mRNA expression for Cdc42 and Duo was reduced in the DLPFC of schizophrenic patients, independently of chronic antipsychotic treatment. Reduced expression of Duo and Cdc42 transcripts was associated with reduced formation of new spines, and with impaired maintenance and plasticity of mature spines, respectively, in the DLPFC (see SRF related news story).

While the above findings suggested that these proteins might contribute to spine changes in layer III DLPFC in schizophrenia, the fact that Cdc42 mRNA expression was reduced across layers III to VI suggested additional factors that contributed to lower spine density in schizophrenia. One possible factor was Cdc42 effector protein 3 (Cdc42EP3), which acted downstream of Cdc42 signaling, and was preferentially expressed in layers II and III. Ide and Lewis (2010) showed that transcript levels of Cdc42EP3 were increased in DLPFC of schizophrenic subjects, independently of chronic antipsychotic treatment. Thus, Cdc42 might signal via Cdc42EP3 to contribute to spine deficits observed in layer III DLPFC in schizophrenia.

The third presentation was by Akiko Hayashi-Takagi from Johns Hopkins University, Baltimore, Maryland, and was titled, “Disrupted in synapse by Disrupted-in-Schizophrenia 1 (DISC1): dendritic spine pathogenesis in schizophrenia.” The DISC1 gene was originally discovered in a large Scottish family carrying a translocation mutation. It is now associated with various mental disorders and in multiple populations worldwide, and has been shown to be a multifunctional protein with multiple subcellular localizations and interactions. As discussed above, schizophrenia is associated with reduced spine density in various brain regions. It is also associated with reduced expression of various synaptic proteins, including DISC1 and Kalirin-7 (Kal-7), and Hayashi-Takagi discussed the role of DISC1 in regulating dendritic spines via Kal-7.

Kal-7 is a GDP/GTP exchange factor (GEF) for Rac1, which regulates spine formation in response to neuronal activity. By expressing mutant DISC1 lacking the Kal-7 binding site, Hayashi-Takagi et al. (SRF related news story) showed that Kal-7 regulated spine morphology via its interaction with DISC1 and Rac1. Overexpression of full-length DISC1, but not mutant DISC1, reduced spine size and density in cortical primary neurons in vitro. Conversely, RNAi knockdown of DISC1 in spines of mature neurons increased the size and number of spines, which formed functional synapses and showed increased frequency of mEPSCs. These changes were reversed by overexpression of full-length but not mutant DISC1. Furthermore, overexpression of full-length but not mutant DISC1 increased binding between Kal-7 and PSD-95, a major component of the post-synaptic density at glutamatergic synapses, while DISC1 knockdown reduced their interaction. Full-length DISC1 also reduced activation of Rac1 as well as binding between Rac1 and Kal-7, while DISC1 knockdown enhanced Rac1 activation. These findings suggested that DISC1 acted as a scaffold to mediate the interaction between Kal-7 and PSD-95, to reduce spine size and density via reduction in Kal-7 interaction with Rac1.

Hayashi-Takagi next discussed how neuronal activity modulated these protein interactions. Using electroconvulsive therapy (ECT) as a model of neuronal activation in mice, Hayashi-Takagi et al. found that ECT reduced interactions among DISC1, Kal-7, and PSD-95, and this dissociation was prevented by an NMDA receptor inhibitor. Neurons with knockdown of DISC1 were especially vulnerable to the effects of neuronal activation, and they showed an increase, then decrease, in spine size, as well as reduced mEPSC frequency and amplitude. This effect was consistent with that seen with chronic activation of Rac1. Thus, Kal-7 was likely released from DISC1 in response to NMDA receptor activation, which allowed it to interact with Rac1 to increase spine size and density.

Jeffrey J. Hutsler from the University of Nevada, in Reno, presented the fourth presentation entitled, “Synaptic spine distributions and morphology on cortical projection neurons in autism spectrum disorders.” Autism spectrum disorders (ASDs) have been associated with abnormal cortical connectivity. Specifically, it has been hypothesized that local, short-range connectivity is increased, while long-range connectivity between cortical regions is decreased. In support of this idea, ASDs have also been associated with genetic alterations in synapse-relevant proteins. Here, Hutsler characterized the changes in spine density observed in the cortex in ASDs.

ASD subjects showed greater spine density on pyramidal cells in the frontal (BA9), temporal (BA21), and parietal (BA7) cortices, relative to age-matched controls. These changes were observed in layers II, III, and V, and in the apical, basal, and oblique dendrites, but most prominently in the oblique dendrites in layer II, and in the apical dendrites in layers II and V that were farther away from the soma. This increase in spine density was associated with mental retardation in ASD subjects (Hutsler and Zhang, 2010). It was possible that alterations in synaptic proteins in ASDs led to reduced synaptic pruning during development.

In addition to an increase in spine density, changes in the shape and length of spines were also observed in ASDs. In the frontal and temporal cortices, spines appeared to be shorter, and there were fewer thin spines and spines that possessed heads. Such changes in spine structure likely mediated the alterations in cortical connectivity observed in ASD.

In the fifth presentation, Chen Zhang, who has just moved from Stanford University to Peking University, China, continued the discussion of dendritic spines in ASDs in his talk, “Aberrant neuroligin function in autism.” Neuroligins are synapse-associated proteins that are involved in the formation and maintenance of synaptic structure. Mutations in one of its isoforms, neuroligin-4 (NLGN4), have been associated with ASDs. Overexpression of this gene has been shown to increase the number of excitatory synapses, while reducing the strength of these synapses. Here, Zhang discussed a familial case of ASD, in which two brothers with ASD were carrying a R87W point mutation.

The R87W mutation was found to be a loss-of-function mutation, which arose in the maternal germ line. It impaired the glycosylation processing of the NLGN4 protein in vitro, which destabilized the protein and prevented its transportation from the endoplasmic reticulum to the cell surface. As a result, the mutant NLGN4 protein lacked its synapse-forming activity (Zhang et al., 2009). This NLGN4 mutation has helped to explain the genetic association of NLGN4 with ASD, and has begun to suggest the mechanisms of abnormal spine dynamics in this disorder.

In the final presentation, Peter Penzes discussed the “Regulation of dendritic spine dynamics by autism-associated synaptic molecules.” ASD is associated with increased spine density in the cortex, as previously discussed, and with reduced dendritic branching, which likely leads to abnormal connectivity within the brain. Here, Penzes discussed the role of Epac2, a synaptic signaling protein for which a rare autism-associated mutation has been found in the structural and functional dynamics of dendritic spines in cortical pyramidal cells (Woolfrey et al., 2009).

Epac2 is a synaptic cAMP target and GEF for Rap, which is involved in long-term potentiation and depression, and is enriched in the cortex and cerebellum. Epac2 signaling was found to promote spine remodeling and depression of excitatory transmission, thus allowing synapses to weaken and enhancing spine dynamics. Epac2 activation in cortical pyramidal neurons in vitro induced spine shrinkage and motility, and also removed AMPA receptors from the synapse and depressed excitatory transmission via D1-type dopamine receptors. Conversely, Epac2 inhibition led to enlarged spines and enhanced spine stabilization.

Epac2 was also found to form complexes with neuroligin-1 and 3 in neurons. Neuroligin-3 was found to regulate the subcellular localization and activity of Epac2 by recruiting Epac2 to the plasma membrane and enhancing its Rap-GEF activity independently of cAMP.

Finally, an autism-associated mutation in Epac2, G706R, was found to affect its GEF activity, and in turn altered Rap signaling. It also altered the synaptic protein distribution and was associated with larger spines in the basal dendrites, and likely led to alteration of the circuit connectivity within the brain.—Nao J. Gamo.

Comments on Related News

Related News: Dendritic Spine Research—Putting Meat on the Bones

Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 13 February 2006
Posted 13 February 2006

The formation of dendritic spines during development and their structural plasticity in the adult brain are critical aspects of synaptogenesis and synaptic plasticity. Actin is the major cytoskeletal source of dendritic spines, and polymerization/depolymerization of actin is the primary determinant of spine motility and morphogenesis. Some, but not all, postmortem studies in schizophrenia have identified reduced dendritic spine density in neurons of the hippocampal formation and dorsolateral prefrontal cortex (for review, see Honer et al., 2000); however, little is known about the underlying pathogenic mechanisms affecting synaptic function in the disease.

Many different factors and proteins are known to control dendritic spine development and remodeling (see Ethell and Pasquale, 2005). Comprehensive investigation of the effectors and signaling pathways involved in regulating actin dynamics may provide insight into the molecular mechanisms mediating altered cortical microcircuitry in the disease.

David Lewis and colleagues have previously reported reduced spine density in the basilar dendrites of pyramidal neurons in laminar III of the DLPFC (though this is not clearly a laminar-specific finding). In their current study, Hill et al. extended these investigations to examine gene expression levels for members of the RhoGTPase family of intracellular signaling molecules (e.g., Cdc42, Rac1, RhoA, Duo), and Debrin, an F-actin binding protein, all of which are critical signal transduction molecules involved in spine formation and maintenance. Their aim was to determine whether alterations in the expression of one of more molecules may underlie the reduced spine density seen in the disorder. Hill et al. report that reductions in Cdc42 and Duo mRNA are observed in the DLPFC in schizophrenia and correlate with spine density on deep layer III pyramidal neurons. This paper provides preliminary evidence that "gene expression levels of certain mRNAs encoding proteins known to be key regulators of dendritic spines are reduced in the DLPFC in schizophrenia." However, the paper also reports that these two mRNAs are reduced in lamina where significant reductions in spine density are not observed in schizophrenia. These results may suggest, as the authors discuss, that reduced expression of Cdc42 and Duo might contribute to, but is not sufficient to cause reduced, spine density.

Synaptic dysfunction has received increasing attention as a key feature of schizophrenia’s neuropathology and possibly its genetic etiology (Law et al., 2004). Neuregulin 1 (NRG1), a lead schizophrenia susceptibility gene, is known to be a critical upstream regulator of signal transduction pathways modulating cytoskeletal dynamics, playing pivotal roles in synapse formation and function. We have previously reported that isoform-specific alterations of the NRG1 gene and its primary receptor, ErbB4, are apparent in the brain in schizophrenia and related to genetic risk for the disease (Law et al, 2005a, Law et al, 2005b). Altered NRG1/ErbB4 signaling in schizophrenia may be a pathway to aberrant cortical neurodevelopment and synaptic function via dysregulation of specific intracellular signaling pathways linked to actin. The lack of significant alterations in gene expression levels for proteins such as Rac1 and RhoA in the DLPFC (gray matter, as reported by Hill and colleagues) in schizophrenia might be because the primary defect may not lie with the expression of these molecules but with the upstream modulation of their function and activity. Therefore, investigation of the proteins themselves, their phosphorylation status and activity, will be useful in understanding how genes effect molecular pathways that mediate biological risk for schizophrenia. The study of intracellular signaling cascades may be a route to a closer understanding of the biological mechanisms underpinning the association of genes such as NRG1 and ErbB4 with schizophrenia and their relationship to its neuropathology.


Ethell IM, Pasquale EB. Molecular mechanisms of dendritic spine development and remodeling. Prog Neurobiol. 2005 Feb;75(3):161-205. Epub 2005 Apr 2. Review. Abstract

Honer G, Young C, and Falkai P, 2000. Synaptic Pathology in the Neuropathology of Schizophrenia, Progress and interpretation. Oxford University Press, edited by Paul J Harrison and Gareth W. Roberts, pp105-136.

Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ. Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry. 2004 Oct;161(10):1848-55. Abstract

Law, 2005a. Soc Neurosci Abstract, SFN Annual Meeting, Washington DSC, 2005. Neuregulin1 and schizophrenia: A pathway to altered cortical circuits. Also See SfN 2005 research news: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize.

Law 2005b ACNP Abstract, Neuropsychopharmacology, vol. 30, Supplement 1. SNPing away at NRG1 and ErbB4 gene expression in schizophrenia.

View all comments by Amanda Jayne Law

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 22 April 2006
Posted 22 April 2006
  I recommend the Primary Papers

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Stephan Heckers, SRF Advisor
Submitted 29 April 2006
Posted 29 April 2006
  I recommend the Primary Papers

The gene Neuregulin 1 (NRG1) on chromosome 8p has been identified as one of the risk genes for schizophrenia. It is unclear how the DNA sequence variation linked to schizophrenia leads to abnormalities of mRNA expression. This would be important to know, in order to understand the downstream effects of the neuregulin gene on neuronal functioning in schizophrenia.

Law and colleagues explored this question in post-mortem specimens of the hippocampus of control subjects and patients with schizophrenia. This elegant study of the expression of four types of NRG1 mRNA (types I-IV) is exactly what we need to translate findings from the field of human genetics into the field of schizophrenia neuropathology. The findings are complex and cannot be translated easily into a model of neuregulin dysfunction in schizophrenia. I would like to highlight two findings.

First, the level of NRG1 type I mRNA expression was increased in the hippocampus of schizophrenia patients. This confirms an earlier study of NRG1 mRNA expression in schizophrenia. It remains to be seen how this change in NRG1 type I mRNA expression relates to the finer details of neuregulin dysfunction in schizophrenia.

Second, one single nucleotide polymorphism (SNP8NRG243177) of the risk haplotype linked to schizophrenia in earlier studies predicts NRG1 type IV mRNA expression. The SNP determines a binding site for transcription factors, providing clues for how DNA sequence variation may lead, via modulation of mRNA expression, to neuronal dysfunction in schizophrenia. It is exciting to see that we can now test specific hypotheses of molecular mechanisms in the brains of patients who have suffered from schizophrenia. The study by Law et al. is an encouraging step in the right direction.

View all comments by Stephan Heckers

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Bryan Roth, SRF Advisor
Submitted 5 May 2006
Posted 5 May 2006
  I recommend the Primary Papers

I think this is a very interesting and potentially significant paper. It is important to point out, however, that it deals with changes in mRNA abundance rather than alterations in neuregulin protein expression. No measures of isoform protein expression were performed, and it is conceivable that neuregulin isoform protein expression could be increased, decreased, or not changed. A second point is that although statistically significant changes in mRNA were measured, they are modest.

Finally, although multiple comparisons were performed, the authors chose not to perform Bonferroni corrections, noting in the primary paper that, "Correction for random effects, such as Bonferroni correction, would be an excessively conservative approach, particularly given that we have restricted our primary analyses to planned comparisons (based on strong prior clinical association and physical location of the SNPs) of four SNPs and a single haplotype comprised of these SNPs. Because the SNPs are in moderate LD, the degree of independence between markers is low and, therefore, correcting for multiple testing would result in a high type II error rate. The prior probability and the predictable association between the deCODE haplotype and expression of NRG1 isoforms (especially type IV, which is its immediate physical neighbor) combined with the LD between SNPs in this haplotype makes statistical correction for these comparisons inappropriate. Nevertheless, our finding regarding type IV expression and the deCODE haplotype and SNP8NRG243177 requires independent replication."

It will thus be important to determine if these changes in neuregulin mRNA isoform abundance are mirrored by significant changes in neuregulin isoform protein expression and if the findings can be independently replicated with other cohorts.

View all comments by Bryan Roth

Related News: Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression

Comment by:  Patricia Estani
Submitted 9 June 2007
Posted 10 June 2007
  I recommend the Primary Papers

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Ali Mohamad Shariaty
Submitted 14 July 2007
Posted 14 July 2007

It is really a fascinating article which is a step towards understanding the molecular mechanisms underlying phenotypes of schizophrenia. Relating genotypes to phenotypes is really necessary for untangling the puzzle of a complex disorder. However, when a regulatory SNP interferes with normal binding of a transcription factor, is it understood that the transcription factor should play a role in brain and therefore in the molecular pathology of schizophrenia? Is there any direct role for involvement of serum response factor (SRF) in brain development or any neurological process?

View all comments by Ali Mohamad Shariaty

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 14 July 2007
Posted 15 July 2007

In response to Ali Mohamad Shariaty’s comment: Serum response factor (SRF) plays a key role in regulating the transcription of a number of genes involved in brain development. Genetic manipulation of SRF has revealed a direct role for it as a regulator of cortical and hippocampal function (e.g., Etkin et al., 2006) influencing both learning and memory. At the cellular level SRF has been shown to regulate dendritic morphology and neuronal migration. Therefore, SRF is indeed an important neurodevelopmental molecule, mediated via its regulation of genes, such as NRG1. Genetic variations that are predicted to interfere with SRF binding (such as the SNP characterized in our study) may affect critical aspects of brain development and function that contribute to schizophrenia. Since SRF regulates the expression of a number of genes, beyond that of NRG1, its involvement in schizophrenia is likely mediated “indirectly” via its effects on the regulation of genes associated with the disorder.


Etkin A, Alarcón JM, Weisberg SP, Touzani K, Huang YY, Nordheim A, Kandel ER. A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Neuron. 2006 Apr 6;50(1):127-43. Abstract

View all comments by Amanda Jayne Law

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Robert Hunter
Submitted 17 July 2007
Posted 17 July 2007
  I recommend the Primary Papers

Related News: DISC1 and SNAP23 Emerge In NMDA Receptor Signaling

Comment by:  Jacqueline Rose
Submitted 2 March 2010
Posted 2 March 2010
  I recommend the Primary Papers

The newly published paper by Katherine Roche and Paul Roche reports SNAP-23 expression in neuron dendrites and examines the possible role of this neuronal SNAP-23 protein. To this point, SNAP-23 has traditionally been discussed in reference to vesicle trafficking in epithelial cells (see Rodriguez-Boulan et al., 2005 for review), so it is of interest to determine the function of SNAP-23 in neurons. Suh et al. report that surface NMDA receptor expression and NMDA-mediated currents are inhibited following SNAP-23 knockdown. Further, SNAP-23 knockdown results in a specific decrease in NR2B subunit insertion; previously, the NR2B subunit has been reported to preferentially localize to recycling endosomes compared to NR2A (Lavezzari et al., 2004). Given these findings, it is reasonable to conclude that SNAP-23 may be involved in maintaining NMDA receptor surface expression possibly by binding to NMDA-specific recycling endosomes.

Interestingly, there is recent evidence that PKC-induced NMDA receptor insertion is mediated by another neuronal SNARE protein; postsynaptic SNAP-25 (Lau et al., 2010). It is possible that activity-induced NMDA receptor trafficking is mediated by SNAP-25, while baseline maintenance of NMDA receptor levels relies on SNAP-23. Other evidence to suggest a strictly regulatory role for SNAP-23 in neuronal NMDA insertion is the finding that activity-dependent receptor insertion from early endosomes has previously been reported to be restricted to AMPA-type glutamate receptors (Park et al., 2004). However, it is possible that activity-induced insertion of AMPA receptors occurs via a distinct endosome pool than NMDA receptors; AMPA and NMDA receptor trafficking has been reported to proceed by distinct vesicle trafficking pathways (Jeyifous et al., 2009).

Although SNAP-23 may not be involved in activity-dependent early endosome receptor trafficking, it is possible that SNAP-23 operates in other pathways linked to activity-induced NMDA receptor trafficking. For instance, SNAP-23 may be the SNARE protein by which lipid raft shuttling of NMDA receptors occurs. SNAP-23 has been found to preferentially associate with lipid rafts over SNAP-25 in PC12 cells (Salaün et al., 2005). As well, NMDA receptors have been found to associate with lipid raft associated proteins flotilin-1 and -2 in neurons (Swanwick et al., 2009). Lipid raft trafficking of NMDA receptors to post-synaptic densities has been reported to follow global ischemia (Besshoh et al., 2005), and the possibility remains that under certain circumstances, NMDA trafficking occurs by lipid raft association to SNAP-23.

Taken together, the discovery of post-synaptic SNARE proteins offers several avenues of research to determine their roles and functions in glutamatergic synapse organization. Further, investigating disruption of synaptic receptor organization presents several possibilities for potential etiologies of disorders linked to compromised glutamate signaling like schizophrenia.


Besshoh, S., Bawa, D., Teves, L., Wallace, M.C. and Gurd, J.W. (2005). Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Journal of Neurochemistry, 93: 186-194. Abstract

Jeyifous, O., Waites, C.L., Specht, C.G., Fujisawa, S., Schubert, M., Lin, E.I., Marshall, J., Aoki, C., de Silva, T., Montgomery, J.M., Garner, C.C. and Green, W.N. (2009). SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature Neuroscience, 12: 1011-1019. Abstract

Lau, C.G., Takayasu, Y., Rodenas-Ruano, A., Paternain, A.V., Lerma, J., Bennet, M.V.L. and Zukin, R.S. (2010). SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. Journal of Neuroscience, 30: 242-254. Abstract

Lavezzari, G., McCallum, J., Dewey, C.M. and Roche, K.W. (2004). Subunit-specific regulation of NMDA receptor endocytosis. Journal of Neuroscience, 24: 6383-6391. Abstract

Park, M., Penick, E.C., Edward, J.G., Kauer, J.A. and Ehlers, M.D. (2004). Recycling endosomes supply AMPA receptors for LTP. Science, 305: 1972-1975. Abstract

Rodriguez-Boulan, E., Kreitzer, G. and Müsch, A. (2005) Organization of vesicular trafficking in epithelia. Nature Reviews: Molecular Cell Biology, 6: 233-247. Abstract

Salaün, C., Gould, G.W. and Chamberlain, L.H. (2005). The SNARE proteins SNAP-25 and SNAP-23 display different affinities for lipid rafts in PC12 cells. Journal of Biological Chemistry, 280: 1236-1240. Abstract

Suh, Y.H., Terashima, A., Petralia, R.S., Wenthold, R.J., Isaac, J.T.R., Roche, K.W. and Roche, P.A. (2010). A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci. 2010 Mar;13(3):338-43. Abstract

Swanwick, C.C., Shapiro, M.E., Chang, Y.Z. and Wenthold, R.J. (2009). NMDA receptors interact with flotillin-1 and -2, lipid raft-associated proteins. FEBS Letters, 583: 1226-1230. Abstract

View all comments by Jacqueline Rose