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The function of the brain depends on highly specific patterns of connections between populations of neurons. The establishment of these connections requires the targeting of axons and dendrites to defined zones or laminae, the recognition of individual target cells, the formation of synapses on particular regions of the dendritic tree, and the diff...
Contexts in source publication
Context 1
... to neuroligins, neurexins bind a structurally unrelated, leucine-rich repeat containing postsynaptic cell adhesion molecule called LRRTM2 (de Wit et al., 2009;Ko et al., 2009). Neurexin-LRRTM2 binding is also regulated by alternative splicing since only neurexins lacking the SS#4 insert bind LRRTM2 ( Ko et al., 2009;Siddiqui et al., 2010) (Fig. 4). This differs from the binding of neuroligins to neurexins, which is modulated by SS#4 but not in an all-or-none fashion (Boucard et al., 2005;Comoletti et al., 2006). Furthermore, binding of LRRTMs or neuroligins to neurexin is mutually exclusive and suggests that these ligands compete for neurexin binding ( Ko et al., 2009;Siddiqui ...
Context 2
... indirectly recruit ion channels and neurotransmitter receptors to the synapse. Indeed, β-neurexin-induced clustering of neuroligins results in co-clustering of NMDARs but not AMPARs ( Graf et al., 2004;Nam and Chen, 2005), and neuroligin-1 knockout mice have decreased NMDAR but not AMPAR-dependent synaptic transmission ( Chubykin et al., 2007) (Fig. 4). LRRTM2 also interacts with PSD-95 through its C-terminal PDZ domain binding motif and binds NMDAR and AMPAR subunits in heterologous cells (de Wit et al., 2009;Linhoff et al., 2009). Artificial aggregation of transfected LRRTM2 on the dendritic surface induces co-clustering of the NMDA receptor subunit NR1 ( Linhoff et al., 2009), ...
Context 3
... (de Wit et al., 2009;Linhoff et al., 2009). Artificial aggregation of transfected LRRTM2 on the dendritic surface induces co-clustering of the NMDA receptor subunit NR1 ( Linhoff et al., 2009), suggesting that LRRTM2 can organize postsynaptic differentiation through recruitment of postsynaptic scaffolding proteins and neurotransmitter receptors (Fig. 4). Consistent with a role in regulating postsynaptic differentiation, lentiviral-mediated knockdown of LRRTM2 in hippocampal granule cells in vivo strongly reduces evoked AMPAR and NMDAR-mediated transmission compared to neighboring uninfected cells (de Wit et al., 2009). The differential effects of neuroligin and LRRTM2 on recruitment ...
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Citations
... There is now a considerable body of research investigating the normal developmental mechanisms that influence neurogenesis, neuronal polarity, process expression, axon guidance, laminar-specific innervation, and the subsequent recognition and formation of synaptic contacts with appropriate target neurons (e.g., Williams et al., 2010;Banerjee et al., 2016;Villalba et al., 2021;Zang et al., 2021;Qi et al., 2022). Historically, the experimental fetal graft approach has proved to be a useful tool in studying the limits of neural plasticity and capacity for repair in developing and adult brains. ...
Data from studies analyzing the differentiation and functional connectivity of embryonic neural tissue grafted into the mammalian nervous system has led to the clinical testing of the fetal graft approach in patients with neurodegenerative disease. While some success has been achieved, ethical concerns have led to a search for alternative therapeutic strategies, mostly exploring the use of neural precursors or neurons derived from pluripotent stem cells to replace damaged host neurons and restore lost circuitries. These more recent studies address questions of graft viability, differentiation, and connectivity similar to those posed by researchers in earlier fetal transplant work, thus reviews of the fetal graft literature may inform and help guide ongoing research in the stem cell/organoid field. This brief review describes some key observations from research into the transplantation of neural tissue into the rat visual system, focusing on grafts of the fetal superior colliculus (tectal grafts) into neonatal or adult hosts. In neonate hosts, grafts quickly develop connections with the underlying host midbrain and attain a morphology typical of mature grafts by about 2 weeks. Grafts consistently contain numerous localized regions which, based on neurofibrillar staining, neuronal morphology (Golgi), neurochemistry, receptor expression, and glial architecture, are homologous to the stratum griseum superficiale of normal superior colliculus. These localized “patches” are also seen after explant culture and when donor tectal tissue is dissociated and reaggregated prior to transplantation. In almost all circumstances, host retinal innervation is restricted to these localized patches, but only those that are located adjacent to the graft surface. Synapses are formed and there is evidence of functional drive. The only exception occurs when Schwann cells are added to dissociated tecta prior to reaggregation. In these co-grafts, the peripheral glia appear to compete with local target factors and host retinal ingrowth is more widespread. Other afferent systems (e.g., host cortex, serotonin) show different patterns of innervation. The host cortical input originates more from extrastriate regions and establishes functional excitatory synapses with grafted neurons. Finally, when grafted into optic tract lesions in adult rat hosts, spontaneously regrowing host retinal axons retain the capacity to selectively innervate the localized patches in embryonic tectal grafts, showing that the specific affinities between adult retinal axons and their targets are not lost during regeneration. While the research described here provides some pertinent information about development and plasticity in visual pathways, a more general aim is to highlight how the review of the extensive fetal graft literature may aid in an appreciation of the positive (and negative) factors that influence survival, differentiation, connectivity and functionality of engineered cells and organoids transplanted into the central nervous system.
... SAMs are integral to organizing synaptic junctions, mediating synaptic transmission and plasticity (Missler et al., 2012;Jang et al., 2017;Südhof, 2018;Kim et al., 2021;Südhof, 2021). Synapses are the most fundamental structures that connect neurons into circuits by enabling the transfer of information, while simultaneously processing this information during transfer; thus governing cognition and behavior (Williams et al., 2010;Bargmann, 2012;Bargmann and Marder, 2013;Di Cristo and Chattopadhyaya, 2020;Sanes and Zipursky, 2020). Normal brain development is accompanied by dynamic synaptic changes which regulate a balance of excitatory glutamatergic and inhibitory GABAergic neuronal firing (E/I balance). ...
Over the past 3 decades, the prevalence of autism spectrum disorder (ASD) has increased globally from 20 to 28 million cases making ASD the fastest-growing developmental disability in the world. Neurexins are a family of presynaptic cell adhesion molecules that have been increasingly implicated in ASD, as evidenced by genetic mutations in the clinical population. Neurexins function as context-dependent specifiers of synapse properties and critical modulators in maintaining the balance between excitatory and inhibitory transmission (E/I balance). Disrupted E/I balance has long been established as a hallmark of ASD making neurexins excellent starting points for understanding the etiology of ASD. Herein we review neurexin mutations that have been discovered in ASD patients. Further, we discuss distinct synaptic mechanisms underlying the aberrant neurotransmission and behavioral deficits observed in different neurexin mouse models, with focus on recent discoveries from the previously overlooked neurexin-2 gene ( Nrxn2 in mice and NRXN2 in humans). Hence, the aim of this review is to provide a summary of new synaptic insights into the molecular underpinnings of ASD.
... Among them, specifically, Nlgn3 showed robust increase after PBM and silencing the Nlgn3 reversed the positive effect of PBM in in vitro. Cell adhension molecules play critical roles in determining synapse specificity by mediating the initial target recognition between pre-and post-synaptic neurons during synapse formation [83,84]. Synaptic components exist in abundance at pre-and post-synaptic terminals in the early stages of synapse development with the support of cell adhesion molecules interactions [85,86]. ...
Background
Temporal lobe epilepsy (TLE) remains one of the most drug-resistant focal epilepsies. Glutamate excitotoxicity and neuroinflammation which leads to loss of synaptic proteins and neuronal death appear to represent a pathogen that characterizes the neurobiology of TLE. Photobiomodulation (PBM) is a rapidly growing therapy for the attenuation of neuronal degeneration harboring non-invasiveness benefits. However, the detailed effects of PBM on excitotoxicity or neuroinflammation remain unclear. We investigated whether tPBM exerts neuroprotective effects on hippocampal neurons in epilepsy mouse model by regulating synapse and synapse-related genes.
Methods
In an in vitro study, we performed imaging analysis and western blot in primary hippocampal neurons from embryonic (E17) rat pups. In an in vivo study, RNA sequencing was performed to identify the gene regulatory by PBM. Histological stain and immunohistochemistry analyses were used to assess synaptic connections, neuroinflammation and neuronal survival. Behavioral tests were used to evaluate the effects of PBM on cognitive functions.
Results
PBM was upregulated synaptic connections in an in vitro. In addition, it was confirmed that transcranial PBM reduced synaptic degeneration, neuronal apoptosis, and neuroinflammation in an in vivo. These effects of PBM were supported by RNA sequencing results showing the relation of PBM with gene regulatory networks of neuronal functions. Specifically, Nlgn3 showed increase after PBM and silencing the Nlgn3 reversed the positive effect of PBM in in vitro. Lastly, behavioral alterations including hypoactivity, anxiety and impaired memory were recovered along with the reduction of seizure score in PBM-treated mice.
Conclusions
Our findings demonstrate that PBM attenuates epileptic excitotoxicity, neurodegeneration and cognitive decline induced by TLE through inhibition of the Nlgn3 gene decrease induced by excitotoxicity.
Graphical Abstract
... A mature dendritic morphology is acquired through multiple consecutive steps: In the initial step, primary dendrites extend away from the cell body to target fields (Kim and Chiba, 2004;Whitford et al., 2002); In the elongation step, dendrites undergo branching, extension, and retraction events to cover the target fields (Jan and Jan, 2010;Tavosanis, 2021); In the final step, self-avoidance and tiling mechanisms prevent dendritic receptive fields from overlapping with neighbors (Grueber and Sagasti, 2010;Parrish et al., 2007;Zipursky and Grueber, 2013). Terminal and intermediate branches are patterned by a combination of genetic instructions, substrate interactions, and neuronal activity (Williams et al., 2010;Wong and Ghosh, 2002). Over the past decades, extracellular signals, cell surface receptors, and intracellular regulators were identified to size and shape higher-order branches across different systems (Dong et al., 2015). ...
The formation of primary dendrites (dendritogenesis) significantly affects the overall orientation and coverage of dendritic arborization, limiting the number and types of inputs a neuron can receive. Previously we reported how a Drosophila motoneuron spatially controls the positioning of dendritogenesis through the Dscam1/Dock/Pak1 pathway; however, how the neuron defines the timing of this process remains elusive. Here we show that the Eph receptor tyrosine kinase provides a temporal cue. We find that, at the onset of dendritogenesis, the Eph receptor recruits the Rho Family GEF Vav to the intracellular domain of Eph, which transiently activates the Cdc42 family of small GTPase. We also show that vap33 (vesicle-associated membrane protein-associated protein) mutants exhibit defects in Cdc42 activation and dendritic outgrowth, indicating Vap33 may play an upstream role in Eph signaling. Together, our result and previous studies argue that the formation of primary dendrites requires the proximity of active Cdc42 and membrane-anchored Pak1 driven by collaborative action between two distinct signaling complexes, Vap33/Eph/Vav and Dscam1/Dock. Signal integration from multiple input pathways would represent a general mechanism for the spatiotemporal precision of dendrite branch formation.
... Especially cerebellar development concurs with childhood, being completed at about puberty [8,22]. This is reflected by paediatric motor coordination approaching the adult standards by 16 years of age [3,5,[23][24][25][26][27]. As the SARA is originally designed to measure cerebellar function in the adult, and as cerebellar motor output is related with cerebellar development, it is thus no surprise that immaturity may confound SARA-scores by representing "physiological brain development" instead of "ataxia" [5]. ...
Introduction
In young children with early onset ataxia (EOA), quantitative rating of ataxia by the Scale for Assessment and Rating of Ataxia (SARA) is longitudinally influenced by the physiological age effect on motor coordination. To enable longitudinal quantitative interpretation of ataxia by SARA in children with EOA, the EPNS ataxia working group has previously determined SARA-scores in typically developing children (4–16 years of age). In toddlers, this information is still lacking. We therefore aimed to investigate the feasibility and reliability of SARA-scores in typically developing toddlers.
Methods
In 57 typically developing toddlers (2–4 years), we aimed to determine the: 1. feasibility of SARA-scores, 2. age-related pre-requisites to obtain SARA-scores in toddlers over all domains, 3. SARA-score reliability, 4. mathematical age connection of SARA-scores in toddlers and older children.
Results
In typically developing toddlers, the feasibility of SARA is strongly age-dependent (p < .000). After computing compensations for two age-related, unfeasible and therefore un-assessable kinetic subtasks and after allowing the videotaping of non-kinetic SARA sub-task performances at home, the SARA was fully reliably assessable in all (n = 57) toddlers (ICC = 0.732). From two to 16 years of age, SARA-scores were mathematically represented by one continuous, exponentially decreasing trend line approaching the adult-optimum at 16 years of age.
Conclusion
In toddlers, SARA-scores are reliably assessable, by using two age-compensations and allowing the videotaping of SARA-performances partly at home. In children with EOA, these data enable longitudinal quantification and interpretation of quantitative ataxia-scores by SARA from 2 years of age throughout childhood.
... The expression of CSPG core proteins and GAG chains shapes the embryonic, postnatal, and adult stages of brain development [8,61], by influencing cell migration, differentiation, and maturation [62]. Additionally, recent evidence suggests that aging increases the protein content of CSPGs in the brain and this correlates with a number of age-dependent structural and physiological changes [7]. ...
Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related genes in the hippocampus of young, aged and very aged mice. ECM gene expression was downregulated, despite the accumulation of ECM proteoglycans during aging. The most robustly downregulated gene was carbohydrate sulfotransferase 3 (Chst3), the enzyme responsible for the chondroitin 6-sulfation (C6S) of proteoglycans. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of the Chst3 gene, resulting in the downregulation of Chst3 expression in non-neuronal cells. Cluster analysis revealed that the expression of lecticans—substrates of CHST3—is tightly co-regulated with this enzyme. These changes in ECM-related genes were accompanied by an age-confounded decline in cognitive performance. Despite the co-directional impairment in cognitive function and average Chst3 expression in the studied age groups, at the individual level we found a negative correlation between mRNA levels of Chst3 and cognitive performance within the very aged group. An analysis of correlations between the expression of ECM-related genes and cognitive performance in novel object versus novel location recognition tasks revealed an apparent trade-off in the positive gene effects in one task at the expense of another. Further analysis revealed that, despite the reduction in the Chst3 mRNA, the expression of CHST3 protein is increased in glial cells but not in neurons, which, however, does not lead to changes in the absolute level of C6S and even results in the decrease in C6S in perineuronal, perisynaptic and periaxonal ECM relative to the elevated expression of its protein carrier versican.
... Synapse assembly and maturation are orchestrated by secreted, transmembrane, and intracellular proteins that guide axons to their targets, mediate initial connections, and recruit organizing molecules to active zones and opposed postsynaptic sites (Cohen-Cory, 2002;Tada and Sheng, 2006;Shen and Scheiffele, 2010;Kolodkin and Tessier-Lavigne, 2011;Krueger et al., 2012;Sudhof, 2012). Scaffold proteins containing PDZ domains play critical roles in this process to ensure synaptic efficiency and fidelity (Garner et al., 2000(Garner et al., , 2002Sheng and Sala, 2001;Feng and Zhang, 2009;Williams et al., 2010;Emes and Grant, 2012). Typically, PDZ-domain-containing proteins are able to bind with short peptide motifs of other proteins that are targeted to a restrictive subcellular site of functional receptors or channels to perform a specific function (Garner et al., 2000;Nourry et al., 2003;Kim and Sheng, 2004;Feng and Zhang, 2009). ...
Postsynaptic structure assembly and remodeling are crucial for functional synapse formation during the establishment of neural circuits. However, how the specific scaffold proteins regulate this process during the development of the postnatal period is poorly understood. In this study, we find that the deficiency of ligand of Numb protein X 1 (Lnx1) leads to abnormal development of dendritic spines to impair functional synaptic formation. We further demonstrate that loss of Lnx1 promotes the internalization of EphB receptors from the cell surface. Constitutively active EphB2 intracellular signaling rescues synaptogenesis in Lnx1 mutant mice. Our data thus reveal a molecular mechanism whereby the Lnx1-EphB complex controls postsynaptic structure for synapse maturation during the adolescent period.
... In addition to Nrxns and Nlgns, other cellsurface proteins have been described to regulate topographic wiring and assembly of specific neural circuits, including latrophilin-2 for layer III entorhinal cortex (EC)-hippocampal CA1 and teneurin-3 for proximal CA1-distal subiculum (6,7). Although these proteins determine synaptic specificity, consistent with their distribution at specific synapses, the prediction of the putative function of specific synaptic CAMs at specific neural circuits is not always straightforward (8)(9)(10). ...
Significance
The present study utilized imaging, electrophysiology, and three-dimensional high-resolution electron microscopy analyses to address the neural circuit role of LRRTM3 in vivo, using both conventional and conditional Lrrtm3 -KO mice. We found that LRRTM3 is required for the specific assembly and function of the medial perforant path to dentate gyrus synapses. Moreover, LRRTM3 is required for proper excitatory synaptic connectivity and long-term synaptic plasticity at mossy fiber–CA3 synapses. Strikingly, presynaptic inactivation of medial perforant path–dentate gyrus (MPP–DG) circuit activities completely rescued the impaired excitatory synaptic inputs and long-term synaptic plasticity of Lrrtm3 -KO mice, demonstrating that LRRTM3 is involved in activity-dependent hippocampal excitatory synapse refinement/stabilization, which is dictated and synchronized by glutamatergic neurotransmission.
... Trillions of synaptic connections are established with exquisite specificity during the patterning of the vertebrate nervous system. During neural development, axons follow guidance cues to extend away from their point of origin to connect to the appropriate lamina (1,2). Once in proximity of the target area, axons select one particular cell or group of cells among many possible choices to initiate synapse formation. ...
Contactins (CNTN) are neural cell adhesion molecules that encode axon-target specificity during the patterning of the vertebrate visual and olfactory systems. Because CNTNs are tethered to the plasma membrane by a glycosylphosphatidylinositol anchor, they lack an intracellular region to communicate across the membrane. Instead, they form co-receptor complexes with distinct transmembrane proteins to transmit signals inside the cell. In particular, a complex of CNTN4 and amyloid precursor protein (APP) is known to guide the assembly of specific circuits in the visual system. Here, using in situ hybridization in zebrafish embryos, we show that CNTN4, CNTN5, and the APP homologues APLP1 and APLP2 are expressed in olfactory pits, suggesting that these receptors may also function together in the organization of olfactory tissues. Furthermore, we use biochemical and structural approaches to characterize interactions between members of these two receptor families. In particular, APP and APLP1 interact with CNTN3-5, while APLP2 only binds to CNTN4 and 5. Finally, structural analyses of five CNTN/amyloid pairs indicate that these proteins interact through a conserved interface involving the second fibronectin type III repeat of CNTNs and the copper-binding domain of amyloid proteins. Overall, this work sets the stage for analyzing CNTN/amyloid-mediated connectivity in vertebrate sensory circuits.
... Mirabella et al. demonstrate that transient maternal elevation of IL-6 induces an abnormal, long-lasting increase of excitatory synapses and brain connectivity in the offspring, providing a mechanistic link between maternal immune activation and defects in newborn brain development. INTRODUCTION Synapse formation during brain development is a complex and hierarchically regulated event ensuring proper brain connectivity (Lu et al., 2009;McAllister, 2007;Williams et al., 2010) and correct excitatory/inhibitory (E/I) balance in the adulthood (Cline, 2005;Gatto and Broadie, 2010). Defects in this process result in altered brain development (Courchesne et al., 2007;Supekar et al., 2013) and neurodevelopmental disorders (Melom and Littleton, 2011;Penzes et al., 2011) . ...
Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.
