Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function

Connor, Steven A.; Ammendrup-Johnsen, Ina; Kishimoto, Yasushi; Tari, Parisa Karimi; Cvetkovska, Vedrana; Harada, Takashi; Ojima, Daiki; Yamamoto, Tohru; Wang, Yu Tian; Craig, Ann Marie

doi:10.1016/j.celrep.2017.11.109

Cited by 43 publications

(64 citation statements)

References 29 publications

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“…Among the transcripts regulated by activity suppression, we found several molecules previously associated with synaptic scaling mechanisms, such as Arc, Bdnf, CamKIIβ, Grin1, Plk2, Rps6ka5, and Rara (SI Appendix, Tables S1 and S2) (24,36,(43)(44)(45)(46)(47)(48). Additionally, the levels of Lrrtm2, Mdga1, Nlgn1, Nlgn3, Npas4, and Syn1, associated with synaptogenesis and stability of excitatory and inhibitory synapses (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59), were also found altered (SI Appendix, Tables S1 and S2), suggesting that homeostatic mechanisms regulating excitatory/inhibitory synaptic balance may also take place with this paradigm of activity blockade (60).…”

Section: Synaptic Scaling Regulates the Neuronal Transcriptome And Mirnamentioning

confidence: 83%

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

Silva

Rodrigues

Fernandes

et al. 2019

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

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Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

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Section: Synaptic Scaling Regulates the Neuronal Transcriptome And Mirnamentioning

confidence: 83%

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

Silva

Rodrigues

Fernandes

et al. 2019

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

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“…Consistent with this notion, IgSF9b was previously proposed to function primarily at inhibitory synapses onto interneurons in hippocampal cultures 14 . In contrast, there is growing evidence that other known synapse organizers such as Nlgn2, MDGA1, and GARLH/LHFPL4 function exclusively at inhibitory synapses onto excitatory neurons 8,44,45 . Together, these findings give rise to the notion that excitatory and inhibitory neurons may utilize an entirely different complement of organizer proteins at inhibitory postsynapses, and that IgSF9b may be the first example of a synapse organizer with specificity for inhibitory synapses onto inhibitory neurons.…”

Section: Discussionmentioning

confidence: 99%

IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses

et al. 2018

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Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.

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“…An appropriate E/I balance is essential for normal adult brain function 54,55 . Thus E/I imbalance affects the normal function and disrupts synchronization between various circuit elements, and can cause autism spectrum disorder (ASD) 56,57 , schizophrenia 58,59 , and Alzheimer's disease (AD) 60 . Indeed, several studies on their model mice have elaborated on the correlation between decreased IPSCs and neuronal death 61,62 .…”

Section: Discussionmentioning

confidence: 99%

Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically expressing PrPLP/Dpl

Kishimoto

Hirono

Atarashi

et al. 2020

Sci Rep

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Prion protein (PrPC) knockout mice, named as the “Ngsk” strain (Ngsk Prnp0/0 mice), show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrPC-like protein (PrPLP/Dpl). Our previous study indicated that the mutant mice also exhibited alterations in cerebellum-dependent delay eyeblink conditioning, even at a young age (16 weeks of age) when neurological changes had not occurred. Thus, this electrophysiological study was designed to examine the synaptic function of the cerebellar cortex in juvenile Ngsk Prnp0/0 mice. We showed that Ngsk Prnp0/0 mice exhibited normal paired-pulse facilitation but impaired long-term depression of excitatory synaptic transmission at synapses between parallel fibres and PCs. GABAA-mediated inhibitory postsynaptic currents recorded from PCs were also weakened in Ngsk Prnp0/0 mice. Furthermore, we confirmed that Ngsk Prnp0/0 mice (7–8-week-old) exhibited abnormalities in delay eyeblink conditioning. Our findings suggest that these alterations in both excitatory and inhibitory synaptic transmission to PCs caused deficits in delay eyeblink conditioning of Ngsk Prnp0/0 mice. Therefore, the Ngsk Prnp0/0 mouse model can contribute to study underlying mechanisms for impairments of synaptic transmission and neural plasticity, and cognitive deficits in the central nervous system.

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Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function

Cited by 43 publications

References 29 publications

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses

Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically expressing PrPLP/Dpl

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