Schizophrenia Research Forum - A Catalyst for Creative Thinking

Architect of Synaptic Plasticity Links Spine Form and Function

30 November 2007. The plasticity of synapses—their ability to change their structure and function in response to activity—is the basis for learning, memory, and associated cognitive skills. Even as the list of neurological conditions that feature defects in plasticity has grown to include mental retardation, depression, drug addiction, and schizophrenia, our understanding of this process is incomplete. Researchers have been unable so far to connect the dots of synaptic potentiation, a transformation that starts with activation of one type of glutamate receptor (the NMDA receptor), continues through reorganization of the synaptic cytoskeleton, and ends with the synaptic enrichment of another glutamate receptor, the AMPA type. Now, Peter Penzes and colleagues at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, have found a molecular missing link that ties the two receptors together directly via the actin cytoskeleton and signaling molecules that regulate it.

In a paper published in the November 21 issue of Neuron, the researchers present evidence that kalirin-7, an activator of the small GTPase Rac-1, is required for both morphological and functional remodeling of synapses in mature cortical neurons. Kalirin-7, they show, is activated by NMDA receptor activation, and associates with AMPA receptors to regulate their density in synapses. The protein thus defines a signaling pathway required for activity-dependent synaptic plasticity, a process the malfunction of which may contribute to schizophrenia. Of particular interest to schizophrenia researchers, kalirin-7 was previously shown to interact with the product of the schizophrenia gene, DISC1 (Millar et al., 2003), and expression of the protein (also known as Duo) is reduced in prefrontal cortex in brains from schizophrenia patients (see SRF related news story).

On the way to altering synapse function, activation of NMDA-type glutamate receptors first causes an enlargement of dendritic spines, the structures that bear synapses. In the new work, lead authors Zhong Xie and Deepak Srivastava trace the pathway controlling this spine enlargement in cultured cortical neurons. They confirm that the change requires activation of the small GTPase Rac-1, a central regulator of the actin cytoskeleton, as well as the activation of the calmodulin-dependent kinase II (CaMKII). They go on to identify kalirin-7, a brain-specific guanine exchange factor, as the substrate of CaMKII that mediates Rac-1 activation and the increase in spine size.

In addition to spine enlargement, kalirin-7 also promotes the increased AMPAR levels that occur in synapses after activation, they find. Surprisingly, the investigators find that kalirin-7 directly associates with the AMPAR, and that this association controls basal levels of the GluR1 receptor subunit and AMPAR-mediated synaptic transmission in mature cortical neurons. In the absence of kalirin-7, the neurons have fewer spines, and show changes in synapse structure, with lower levels of the GluR1 subunit of the AMPAR. Neurons lacking kalirin-7, or treated with a competitor peptide that blocks synaptic location of the protein, do not display increased synaptic strengthening after NMDAR stimulation.

According to the authors, the results demonstrate that normal levels of kalirin expression are required for NMDAR activity-dependent enhancement of AMPAR-mediated synaptic transmission. “Our results, together with the established important roles of the upstream regulators of kalirin-7 (NMDARs and CaMKII) and its targets (Rac-1 and actin) in plasticity, strongly suggest that kalirin-7 may be an important regulator of the experience-dependent modifications of forebrain circuits during postnatal development and may play an important role in learning and memory,” they write. The next step will be to generate kalirin-7-deficient animals to confirm the role of the protein in vivo.—Pat McCaffrey.

Xie Z, Srivastava DP, Photowala H, Kai L, Cahill ME, Woolfrey KM, Shum CY, Surmeier DJ, Penzes P. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron. 2007 Nov 22;56(4):640-56. Abstract

Comments on News and Primary Papers
Comment by:  Akira Sawa, SRF Advisor
Submitted 29 December 2007
Posted 29 December 2007

Synaptic disturbance in the pathology of schizophrenia is a well-established idea. Lewis’s lab has reported decreased synaptic spine density in brains from patients with schizophrenia (Glantz and Lewis, 2000). Although it is unclear whether this is primary or secondary, expression of kalirin-7-associated molecules is decreased (Hill et al., 2006). Thus, kalirin-7-associated cellular signaling in synaptic spines may have implication for the pathology of schizophrenia. In this sense, I regard the recent publication from Penzes’s lab as very interesting in schizophrenia research.

It is still unclear whether kalirin-7 may interact with genetic susceptibility factors for schizophrenia, such as ErbB4 and DISC1. Until the protein interactions are tested by co-immunoprecipitation at endogenous protein levels, as well as validated by cell staining, we cannot tell whether or not such factors are really associated with the kalirin-7 pathway. This putative protein interaction of kalirin-7 with DISC1 or ErbB4 will be an important issue to address in the future.

In Penzes’s neuronal cultures, he has focused on spine formation in pyramidal neurons, but not in interneurons. Thus, the mechanism proposed in his study will be useful to consider possible pathology in pyramidal neurons in brains of patients with schizophrenia.

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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: 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