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Pyramidal neurons (PNs) are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization, but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light–electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 PNs of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.

Integrins connect cells to the extracellular matrix and mediate neuron-neuron or neuron-glia interactions during synapse maturation and synaptic plasticity. Here, Charrier et al . find that integrins β1 and β3 exert opposing actions via CaMKII to regulate glycine receptor lateral diffusion and gephyrin trafficking at the inhibitory synapses in spinal cord neurons. The regulation of glycine receptor (GlyR) number at synapses is necessary for the efficacy of inhibition and the control of neuronal excitability in the spinal cord. GlyR accumulation at synapses depends on the scaffolding molecule gephyrin and is linked to GlyR synaptic dwell time. However, the mechanisms that tune GlyR synaptic exchanges in response to different neuronal environments are unknown. Integrins are cell adhesion molecules and signaling receptors. Using single quantum dot imaging and fluorescence recovery after photobleaching, we found in rats that β1 and β3 integrins adjust synaptic strength by regulating the synaptic dwell time of both GlyRs and gephyrin. β1 and β3 integrins crosstalked via calcium/calmodulin-dependent protein kinase II and adapted GlyR lateral diffusion and gephyrin-dependent trapping at synapses. This provides a mechanism for maintaining or adjusting the steady state of postsynaptic molecule exchanges and the level of glycinergic inhibition in response to neuron- and glia-derived signals or extracellular matrix remodeling.

Pyramidal neurons are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 pyramidal neurons of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually-innervated and 38% of inhibitory synapses localize to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity. Competing Interest Statement The authors have declared no competing interest.

Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny.Competing Interest StatementThe authors have declared no competing interest.

The regulation of glycine receptor (GlyR) number at synapses is necessary for the efficacy of inhibition and the control of neuronal excitability in the spinal cord. GlyR accumulation at synapses depends on the scaffolding molecule gephyrin and is linked to GlyR synaptic dwell time. However, the mechanisms that tune GlyR synaptic exchanges in response to different neuronal environments are unknown. Integrins are cell adhesion molecules and signaling receptors. Using single quantum dot imaging and fluorescence recovery after photobleaching, we found in rats that beta 1 and beta 3 integrins adjust synaptic strength by regulating the synaptic dwell time of both GlyRs and gephyrin. beta 1 and beta 3 integrins crosstalked via calcium/calmodulin-dependent protein kinase II and adapted GlyR lateral diffusion and gephyrin-dependent trapping at synapses. This provides a mechanism for maintaining or adjusting the steady state of postsynaptic molecule exchanges and the level of glycinergic inhibition in response to neuron- and glia-derived signals or extracellular matrix remodeling.

The regulation of glycine receptor (GlyR) number at synapses is necessary for the efficacy of inhibition and the control of neuronal excitability in the spinal cord. GlyR accumulation at synapses depends on the scaffolding molecule gephyrin and is linked to GlyR synaptic dwell time. However, the mechanisms that tune GlyR synaptic exchanges in response to different neuronal environments are unknown. Integrins are cell adhesion molecules and signaling receptors. Using single quantum dot imaging and fluorescence recovery after photobleaching, we found in rats that [beta]1 and [beta]3 integrins adjust synaptic strength by regulating the synaptic dwell time of both GlyRs and gephyrin. [beta]1 and [beta]3 integrins crosstalked via calcium/calmodulin-dependent protein kinase II and adapted GlyR lateral diffusion and gephyrin-dependent trapping at synapses. This provides a mechanism for maintaining or adjusting the steady state of postsynaptic molecule exchanges and the level of glycinergic inhibition in response to neuron- and glia-derived signals or extracellular matrix remodeling.

The regulation of glycine receptor (GlyR) number at synapses is fundamental for the efficacy of inhibition and the control of neuronal excitability in the spinal cord. GlyR accumulation at synapses depends on the scaffolding molecule gephyrin and is linked to GlyR synaptic dwell time. However, the mechanisms that tune GlyR synaptic exchanges depending on the neuronal environment are unknown. Integrins are cell adhesion molecules and signaling receptors. Using single quantum dot and FRAP imaging, we demonstrate in rats that β1 and β3 integrins regulate the synaptic dwell time of both GlyRs and gephyrin to adjust synaptic strength. β1 and β3 integrins crosstalk via calcium/calmodulin-dependent protein kinase II and adapt GlyR lateral diffusion and gephyrin-dependent trapping at synapses. This provides a mechanism to maintain or adjust the steady state of postsynaptic molecule exchanges and the level of glycinergic inhibition in response to neuron- and glia-derived signals or extracellular matrix remodeling.

Neurotransmitter receptors are the linchpin of neuronal communication. These receptors often form large multimeric complexes that differ in their subunit composition, distribution and signaling properties. Studying individual subtypes in native tissues with subunit stoichiometry resolution remains challenging. This is the case of NMDA receptors (NMDARs), a class of glutamate-gated ion channels playing essential roles in brain development and plasticity. These receptors co-exist as multiple subtypes, with GluN1/GluN2A (GluN2A diheteromers), GluN1/GluN2B (GluN2B diheteromers) and GluN1/GluN2A/GluN2B (GluN2A/GluN2B triheteromers) receptors prevailing in the adult forebrain. Despite numerous investigations, the relative abundance and subcellular distribution of these subtypes remain contentious. Here, we designed a photochemical tool (Opto2B) enabling specific and reversible modulation of GluN2B diheteromers, while leaving other receptor subtypes unaffected (in particular GluN2A/GluN2B tri-heteromers). Using Opto2B, we established the differential contribution of GluN2B diheteromers to synaptic and extrasynaptic NMDAR pools during development. In particular, we show that in adult hippocampal CA1 pyramidal cells, GluN2A-receptors predominate in both pools, with no preferential contribution of GluN2B diheteromers to extrasynaptic currents. Our study clarifies decades of controversial research on extrasynaptic NMDARs and paves the way for interrogating NMDAR signaling diversity with unprecedented molecular and spatio-temporal resolution.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Minor modifications in the abstract and change of formatting

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A; yet the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in the Cri-du-Chat syndrome, as an SRGAP2 effector. We demonstrate that CTNND2 slows down synaptic maturation and promotes neuronal homeostasis. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in the synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C enhances CTNND2 synaptic accumulation in human neurons. Our findings reveal that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans, and link human-specific and ID genes at the synapse.

T follicular helper (Tfh) cells are a distinct subset of CD4 T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells.