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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.

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