Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1

Xu, Junyu; Xiao, Nan; Xia, Jun

doi:10.1038/nn.2459

Cited by 176 publications

(158 citation statements)

References 13 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…These findings suggested that NLs require other extracellular ligands besides neurexins. Two proteins, PTPRT and thrombospondin-1, have been reported to regulate synapse formation via direct interactions with NLs in cultured hippocampal neurons (39,40). However, because PTPRT is localized specifically to excitatory synapses, and the localization of thrombospondin-1 at synapses remains unclear, these findings cannot account fully for isoform-dependent differential NL activities in synapse validation.…”

Section: Discussionmentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

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

118

139

View full text Add to dashboard Cite

The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

show abstract

Section: Discussionmentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

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

118

139

View full text Add to dashboard Cite

show abstract

“…In fact, other studies report that abnormal spine density at young ages is rectified at more mature ages (for recent examples see Refs. 71,72). Accordingly, spine density is regulated by several powerful mechanisms that ensure normal density at the adult stage if at all possible.…”

Section: Discussionmentioning

confidence: 99%

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Lü

Zha

Kim

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The A kinase anchor protein AKAP150 recruits the cAMPdependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development.Dendritic spines receive most of the excitatory input in mammalian neurons (1, 2) and compartmentalize signaling that regulates the synaptic response (3, 4). Several protein kinases and phosphatases, including CaMKII, cAMP-dependent protein kinase (PKA), 3 PKC, and protein phosphatase PP2A and PP2B (calcineurin) (5) play prominent roles in synaptic plasticity. Synaptic activity translates into their activation, thereby affecting spine stability, morphology, and postsynaptic responses (6 -13). Spines are dynamically gained and lost during synaptogenesis (9, 14 -16) and in response to neuronal activity (17-19).AKAP150 is a product of the Akap5 gene in mice and is the main AKAP that recruits PKA to postsynaptic sites (20 -25). It binds with its very C terminus to the N-terminal dimerization domain of the regulatory RII subunits of PKA (26,27). It also binds PKC (28), PP2B (29,30), and the SH3-GK region of the postsynaptic scaffolding proteins SAP97 and PSD-95 (31, 32). PSD-95 binds with its PDZ domains to the C-terminal ((S/ T)X(I/V)) motif of NMDA-type glutamate receptor (NMDAR) NR2 subunits (33). PSD-95 also binds to the C terminus of stargazin (␥2) and its homologues ␥3, ␥4, and ␥8, which associate with AMPAR-type glutamate receptor (AMPAR) for postsynaptic localization in conjunction with . SAP97 directly binds to the AMPAR GluR1 subunit via a PDZ-C-terminal interaction (37) to link AKAP150 and thereby PKA, PKC,. Phosphorylation of GluR1 on Ser-845 by PKA can increase channel activity (42) and accumulation of GluR1-containing AMPAR at the postsynaptic site during hippocampal LTP (43, 44) (see also Refs. 45,46). The N terminus of AKAP150 also binds F-actin, cadherin, adenylyl cyclases, and PIP 2 and targets AKAP150 to dendritic spines and the central region binds PSD-...

show abstract

“…Dock4 scramble shRNAs or shRNAs were subcloned to the lentiviral vector pFUGW, which contains a GFP coding sequence separated by an internal ribosome entry site. pFUGW shRNAs were transfected into HEK293T cells together with an HIV-1 packing vector ⌬8.9 and a vesicular stomatitis virus glycoprotein (VSVg) envelope plasmid to generate lentiviral particles as described previously (33).…”

Section: Methodsmentioning

confidence: 99%

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

Xiao

Peng

Wan

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Dock4, a guanine nucleotide exchange factor for Rac1, is associated with neuropsychiatric diseases. Results: Dock4 regulates neurite differentiation in neuroblastoma cells and hippocampal neurons. Conclusion: Dock4 is an important regulator during neural differentiation. Significance: This study contributes to a better understanding of the molecular and cellular events during neural differentiation and may provide new insights into the molecular pathophysiology of neuropsychiatric diseases.

show abstract

Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1

Cited by 176 publications

References 13 publications

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

Contact Info

Product

Resources

About