SALM4 negatively regulates NMDA receptor function and fear memory consolidation

Lie, Eunkyung; Yeo, Yeji; Lee, Eun Jae; Shin, Wangyong; Kim, Kyungdeok; Han, Kyung Ah; Yang, Esther; Choi, Tae Yong; Bae, Moo-Ho; Lee, Suho; Um, Seung Min; Choi, Se Young; Kim, Hyun; Ko, Jaewon; Kim, Eunjoon

doi:10.1038/s42003-021-02656-3

Cited by 3 publications

(1 citation statement)

References 84 publications

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“…For instance, extracellular interactors such as EphB2 (Dalva et al, 2000;Hanamura et al, 2017;Washburn et al, 2020), Nlgn1 (Budreck et al, 2013), and SALM1 (Wang et al, 2006) can impact synaptic NMDAR levels. In addition, NMDAR activity is indirectly regulated by presynaptic cell adhesion molecules, such as Nrxn1 (Dai et al, 2021(Dai et al, , 2019 and LAR-RPTPs (Kim et al, 2020;Lie et al, 2021Lie et al, , 2016Sclip and Südhof, 2020). While these interactors and pathways influence synaptic NMDAR activity, it is untested whether any of these mechanisms are 'bidirectional' -in other words, can NMDARs signal through the same molecular networks that are responsible for recruiting them?…”

Section: Discussionmentioning

confidence: 99%

Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

Dharmasri,

DeMarco,

Anderson

et al. 2024

Preprint

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Nanoscale protein organization within the active zone (AZ) and post-synaptic density (PSD) influences synaptic transmission. Nanoclusters of presynaptic Munc13-1 are associated with readily releasable pool size and neurotransmitter vesicle priming, while postsynaptic PSD-95 nanoclusters coordinate glutamate receptors across from release sites to control their opening probability. Nanocluster number, size, and protein density vary between synapse types and with development and plasticity, supporting a wide range of functional states at the synapse. Whether or how the receptors themselves control this critical architecture remains unclear. One prominent PSD molecular complex is the NMDA receptor (NMDAR). NMDARs coordinate several modes of signaling within synapses, giving them the potential to influence synaptic organization through direct protein interactions or through signaling. We found that loss of NMDARs results in larger synapses that contain smaller, denser, and more numerous PSD-95 nanoclusters. Intriguingly, NMDAR loss also generates retrograde reorganization of the active zone, resulting in denser, more numerous Munc13-1 nanoclusters, more of which are aligned with PSD-95 nanoclusters. Together, these changes to synaptic nanostructure predict stronger AMPA receptor-mediated transmission in the absence of NMDARs. Notably, while prolonged antagonism of NMDAR activity increases Munc13-1 density within nanoclusters, it does not fully recapitulate these trans-synaptic effects. Thus, our results confirm that NMDARs play an important role in maintaining pre- and postsynaptic nanostructure and suggest that both decreased NMDAR expression and suppressed NMDAR activity may exert distinct effects on synaptic function, yet through unique architectural mechanisms.Significance StatementSynaptic transmission is shaped by the trans-synaptic coordination of molecular ensembles required for neurotransmitter release and receptor retention, but how receptors themselves influence this critical architecture remains unclear. Using state-of-the-art super-resolution microscopy, we report that loss of NMDA receptors from excitatory synapses alters both pre- and postsynaptic nano-organizational features. Notably, pharmacological antagonism of NMDA receptors also alters presynaptic features, but without fully mimicking effects of the knockout. This suggests that both NMDA receptor activity and presence at the synapse exert retrograde influence on active zone organization. Because numerous disease and activity states decrease expression or function of NMDA receptors, our results suggest that distinct nanostructural states contribute to the unique functional status of synapses in these disorders.

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Section: Discussionmentioning

confidence: 99%

Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

Dharmasri,

DeMarco,

Anderson

et al. 2024

Preprint

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POU2F1/DNMT3a Pathway Participates in Neuropathic Pain by Hypermethylation-Mediated LRFN4 Downregulation Following Oxaliplatin Treatment

Gu,

Wang,

et al. 2023

Neurochem Res

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Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice

Pan,

Audrain,

Sakakibara

et al. 2024

Front. Aging Neurosci.

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IntroductionDual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer’s disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.MethodsTo investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP.ResultsBarnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1–40 and Aß1–42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of “microglial clusters,” which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD.DiscussionIn summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.

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SALM4 negatively regulates NMDA receptor function and fear memory consolidation

Cited by 3 publications

References 84 publications

Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

POU2F1/DNMT3a Pathway Participates in Neuropathic Pain by Hypermethylation-Mediated LRFN4 Downregulation Following Oxaliplatin Treatment

Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice

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