Persistence of Coordinated Long-Term Potentiation and Dendritic Spine Enlargement at Mature Hippocampal CA1 Synapses Requires N-Cadherin

Bozdagi, Ozlem; Wang, Xiaobin; Nikitczuk, Jessica S.; Anderson, Tonya R.; Bloss, Erik B.; Radice, Glenn L.; Zhou, Qiang; Benson, Deanna L.; Huntley, George W.

doi:10.1523/jneurosci.1223-10.2010

Cited by 111 publications

(136 citation statements)

References 58 publications

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“…This model of synaptic dysfunction is also consistent with the lack of impairment in hippocampal LTP in β-cat Δex3/+ mice; enhanced cadherin stability at the synaptic membrane is unlikely to affect the insertion of additional AMPA receptors to the synaptic membrane, which is the primary mechanism responsible for LTP (34). Interestingly, basal synaptic transmission and postsynaptic strength were unaffected by the stabilization of cadherin in β-cat Δex3/+ mice, and previous studies have shown that knockdown of N-cadherin (35,36) or β-catenin (23) in vivo also did not significantly impact synapse number or basal synaptic transmission. These findings suggest that, although cadherin is important for activity-dependent plasticity, other mechanisms play a more dominant role in determining basal synapse density and synaptic strength.…”

Section: Discussionsupporting

confidence: 87%

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Mills¹,

Bartlett²,

Dissing-Olesen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Complex learning and memory are believed to require the weakening or elimination of synapses in the brain, a process mediated by adhesion molecules, which maintain synapse strength and stability. In the present study, we examine in vivo the effects of stabilization of β-catenin, an intracellular protein that is a component of the cadherin adhesion complex. We find that stabilization of β-catenin in the brain prevents normal activity-dependent downscaling of synapse strength, resulting in a striking impairment in cognitive flexibility. These results demonstrate that β-catenin plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have detrimental effects on cognitive function.

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Section: Discussionsupporting

confidence: 87%

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Mills¹,

Bartlett²,

Dissing-Olesen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…15,27,28 N-cadherin is required for critical brain processes, including long-term potentiation, pre-to post-synaptic adhesion, dendritic spine elongation -thereby regulating glutamate receptor trafficking and neuronal migration. [29][30][31][32] A bioinformatic prediction of the multiple functional associations for CDH2 is provided in Supplementary Figure 2. 33 The CDH2 N845S variant lies in the highly conserved cytoplasmic domain.…”

Section: Resultsmentioning

confidence: 99%

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

et al. 2013

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The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N ¼ 1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P ¼ 0.014, OR ¼ 6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

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“…For example, N-cadherin, one of the best-characterized synaptic adhesion proteins, plays an important role in regulating dendritic spine morphology (38), basal synaptic strength, short-term plasticity, and long-term potentiation (27,(39)(40)(41)(42). Although N-cadherin interacts with a cohort of scaffolding proteins, it also binds directly to GluA2 AMPAR subunit (27,43).…”

Section: Discussionmentioning

confidence: 99%

β3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons

Pozo

Cingolani

Bassani

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The integrins are transmembrane receptors for ECM proteins, and they regulate various cellular functions in the central nervous system. In hippocampal neurons, the β3 integrin subtype is required for homeostatic synaptic scaling of AMPA receptors (AMPARs) induced by chronic activity deprivation. The surface level of β3 integrin in postsynaptic neurons directly correlates with synaptic strength and the abundance of synaptic GluA2 AMPAR subunit. Although these observations suggest a functional link between β3 integrin and AMPAR, little is known about the mechanistic basis for the connection. Here we investigate the nature of β3 integrin and AMPAR interaction underlying the β3 integrin-dependent control of synaptic AMPAR expression and thus synaptic strength. We show that β3 integrin and GluA2 subunit form a complex in mouse brain that involves the direct binding between their cytoplasmic domains. In contrast, β3 integrin associates with GluA1 AMPAR subunit only weakly, and, in a heterologous expression system, the interaction requires the coexpression of GluA2. Surprisingly, in hippocampal pyramidal neurons, expressing β3 integrin mutants with either increased or decreased affinity for extracellular ligands has no differential effects in elevating excitatory synaptic currents and surface GluA2 levels compared with WT β3 integrin. Our findings identify an integrin family member, β3, as a direct interactor of an AMPAR subunit and provide molecular insights into how this cell-adhesion protein regulates the composition of cell-surface AMPARs.homeostatic synaptic plasticity | extracellular matrix | excitatory synaptic transmission S ynapses receive, integrate, and transmit information across neural networks, and use-dependent changes in synaptic efficacy are thought to underlie a variety of brain functions from computations to learning and memory. The activity-dependent changes in synaptic properties rely on the coordinated actions of a vast array of molecules in the pre-and the postsynaptic neurons. At excitatory synapses, changes in postsynaptic AMPA receptor (AMPAR) number are crucial for regulating synaptic strength. Insertion and removal of postsynaptic AMPARs contribute directly to some forms of long-term potentiation and long-term depression (1, 2) and to homeostatic synaptic plasticity, which is a compensatory mechanism engaged by neurons in response to chronic changes in network activity (3, 4). Delineating the mechanisms governing the trafficking of AMPARs is a key step toward understanding the basis of functional plasticity at excitatory synapses.Growing evidence indicates that synaptic cell-adhesion molecules are important players in regulating synaptic plasticity. They bridge pre-and postsynaptic membranes and coordinate morphological and functional synaptic changes across the synaptic cleft (5, 6). In this respect, the integrins are of special interest. They are heterodimers consisting of an α-and a β-subunit, and they mediate cell-ECM and cell-cell adhesions (7). Unlike other cell-adhesion molecules, int...

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Persistence of Coordinated Long-Term Potentiation and Dendritic Spine Enlargement at Mature Hippocampal CA1 Synapses Requires N-Cadherin

Cited by 111 publications

References 58 publications

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

β3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons

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