The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Schmidt, Ewoud R.E.; Kupferman, Justine V.; Stackmann, Michelle; Polleux, Franck

doi:10.1101/596940

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…We would like to thank Dr. Edward Ruthazer for valuable input throughout the course of this study, as well as Dr. Andrew Greenhalgh and Andy YL Gao for a critical review of the manuscript. A version of this article has been released as a bioRxiv preprint at: https://doi.org/10.1101/742148 (Salmon et al, 2019).…”

Section: Data Availability Statementmentioning

confidence: 99%

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Salmon

Pribiag

Gizowski

et al. 2020

Front. Cell. Neurosci.

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γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABA A transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABA A transmission can either drive neural activity or inhibit it through shunting inhibition. The varying roles of depolarizing GABA A transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development when the majority of synapses form and GABA A transmission switches from depolarizing to hyperpolarizing. Here, we addressed the importance of depolarizing but inhibitory (or shunting) GABA A transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABA A transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K + −Cl − co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABA A transmission in CA1 neurons. We found that blocking depolarizing but shunting GABA A transmission increased excitatory synapse number and strength, indicating that depolarizing GABA A transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent but independent of BDNF signaling. Importantly, the elevated number of synapses was stable for more than a week after GABA A inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABA A transmission in shaping excitatory connectivity during neural circuit development.

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Section: Data Availability Statementmentioning

confidence: 99%

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Salmon

Pribiag

Gizowski

et al. 2020

Front. Cell. Neurosci.

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show abstract

“…Co-expression in COS7 cells revealed that SRGAP2C also interacts with SRGAP2A via their F-BAR domain resulting in degradation of the heterodimer product in a proteasome-dependent manner (Schmidt et al, 2019), explaining the mirroring effect between Srgap2-knockdown and SRGAP2C-expressing mice. Moreover, SRGAP2A promotes maturation of excitatory and inhibitory synapses through interaction with key molecular players such as Homer, Gephyrin, and Rac1; functions that are inhibited in the presence of SRGAP2C, leading to delayed neuronal maturation and a higher density of synapses (both excitatory and inhibitory) (Fossati et al, 2016;Schmidt et al, 2019). Further, expression of SRGAP2C in mouse cortical pyramidal neurons resulted in increased long-range synaptic connectivity (Schmidt et al, 2021).…”

Section: Srgap2cmentioning

confidence: 98%

Genomic structural variation: A complex but important driver of human evolution

Soto

Uribe-Salazar

Shew

et al. 2023

American Journal of Biological Anthropology

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Structural variants (SVs)-including duplications, deletions, and inversions of DNA-can have significant genomic and functional impacts but are technically difficult to identify and assay compared with single-nucleotide variants. With the aid of new genomic technologies, it has become clear that SVs account for significant differences across and within species. This phenomenon is particularly well-documented for humans and other primates due to the wealth of sequence data available. In great apes, SVs affect a larger number of nucleotides than single-nucleotide variants, with many identified SVs exhibiting population and species specificity. In this review, we highlight the importance of SVs in human evolution by (1) how they have shaped great ape genomes resulting in sensitized regions associated with traits and diseases, (2) their impact on gene functions and regulation, which subsequently has played a role in natural selection, and (3) the role of gene duplications in human brain evolution. We further discuss how to incorporate SVs in research, including the strengths and limitations of various genomic approaches. Finally, we propose future considerations in integrating existing data and biospecimens with the ever-expanding SV compendium propelled by biotechnology advancements.

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“…Finally, Srgap2, which is downregulated in P07 HU mice, inhibits dendrite branching and synaptogenesis (Charrier et al, 2012). Human-specific duplication of SRGAP2C suppresses activity of SRGAP2, resulting in complex dendrites and a greater density of spines in human (Schmidt et al, 2019;Schmidt et al, 2021).…”

Section: Human Clock Regulates Genes With Human-specific Open Chromatinmentioning

confidence: 99%

An extra-circadian function for human CLOCK in the neocortex

Liu

Fontenot

Kulkarni

et al. 2023

Preprint

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Core circadian-related proteins such as the transcription factor CLOCK are ubiquitously expressed and important for regulating molecular pathways underlying circadian rhythms. Previous work has suggested that CLOCK has evolved human neocortex-specific gene regulation and therefore may have extra-circadian functions. To test this in vivo, we generated a mouse model that recapitulates human cortical expression of CLOCK. The CLOCK humanized (HU) mice show enhanced cognitive flexibility, which is associated with the alteration in spatiotemporal expression of CLOCK. Cell type specific genomic profiling of HU mice identified upregulated genes related to dendritic growth and spine formation in excitatory neurons. Consistent with this result, we found that excitatory neurons in HU mice have increased complexity of dendritic branching and spine density, as well as a greater frequency of excitatory postsynaptic currents, suggesting an increase in neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-induced neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK evolved extra-circadian gains of function via altered spatiotemporal gene expression and these functions may underlie human brain specializations.

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The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Cited by 4 publications

References 27 publications

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Genomic structural variation: A complex but important driver of human evolution

An extra-circadian function for human CLOCK in the neocortex

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