Social isolation causes profound changes in social behaviour in a variety of species. However, the genetic and molecular mechanisms modulating behavioural responses to social isolation and social recovery remain to be elucidated. Here, we quantified the behavioural response of vinegar flies to social isolation using two distinct protocols (social space preference and sociability, the spontaneous tendencies to form groups). We found that social isolation increased social space and reduced sociability. These effects of social isolation were reversible and could be reduced after 3 days of group housing. Flies with a loss of function of neuroligin3 (orthologue of autism-related neuroligin genes) with known increased social space in a socially enriched environment were still able to recover from social isolation. We also show that dopamine (DA) is needed for a response to social isolation and recovery in males but not in females. Furthermore, only in males, DA levels are reduced after isolation and are not recovered after group housing. Finally, in socially enriched flies mutant for neuroligin3, DA levels are reduced in males, but not in females. We propose a model to explain how DA and neuroligin3 are involved in the behavioural response to social isolation and its recovery in a dynamic and sex-specific manner.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.

Autism spectrum disorder (ASD) is a neurodevelopmental illness that leads to repetitive behavior and debilitates social communication. Genetic changes such as susceptible genes and environmental factors promote ASD pathogenesis. Mutations in neuroligins (NLGNs) and neurexin (NRXNs) complex which encode cell adhesion molecules have a significant part in synapses formation, transcription, and excitatory-inhibitory balance. The ASD pathogenesis could partly, at the least, be related to synaptic dysfunction. Here, the NRXNs and NLGNs genes and signaling pathways involved in the synaptic malfunction that causes ASD have been reviewed. Besides, a new insight of NLGNs and NRXNs genes in ASD will be conferred.

BACKGROUND: Neuroligin-3 is a postsynaptic adhesion molecule involved in synapse development and function. It is implicated in rare, monogenic forms of autism, and its shedding is critical to the tumor microenvironment of gliomas. While other members of the neuroligin family exhibit synapse-type specificity in localization and function through distinct interactions with postsynaptic scaffold proteins, the specificity of neuroligin-3 synaptic localization remains largely unknown.
METHODS: We investigated the synaptic localization of neuroligin-3 across regions in mouse and human brain samples after validating antibody specificity in knockout animals. We raised a phospho-specific neuroligin antibody and used phosphoproteomics, cell-based assays, and in utero CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) knockout and gene replacement to identify mechanisms that regulate neuroligin-3 localization to distinct synapse types.
RESULTS: Neuroligin-3 exhibits region-dependent synapse specificity, largely localizing to excitatory synapses in cortical regions and inhibitory synapses in subcortical regions of the brain in both mice and humans. We identified specific phosphorylation of cortical neuroligin-3 at a key binding site for recruitment to inhibitory synapses, while subcortical neuroligin-3 remained unphosphorylated. In vitro, phosphomimetic mutation of that site disrupted neuroligin-3 association with the inhibitory postsynaptic scaffolding protein gephyrin. In vivo, phosphomimetic mutants of neuroligin-3 localized to excitatory postsynapses, while phospho-null mutants localized to inhibitory postsynapses.
CONCLUSIONS: These data reveal an unexpected region-specific pattern of neuroligin-3 synapse specificity, as well as a phosphorylation-dependent mechanism that regulates its recruitment to either excitatory or inhibitory synapses. These findings add to our understanding of how neuroligin-3 is involved in conditions that may affect the balance of excitation and inhibition.

Synapse organizing proteins are multifaceted molecules that coordinate the complex processes of brain development and plasticity at the level of individual synapses. Their importance is demonstrated by the major brain disorders that emerge when their function is compromised. The mechanisms whereby the various families of organizers govern synapses are diverse, but converge on the structure, function, and plasticity of synapses. Therefore, synapse organizers regulate how synapses adapt to ongoing activity, a process central for determining the developmental trajectory of the brain and critical to all forms of cognition. Here, we explore how synapse organizers set the conditions for synaptic plasticity and the associated molecular events, which eventually link to behavioral features of neurodevelopmental and neuropsychiatric disorders. We also propose central questions on how synapse organizers influence network function through integrating nanoscale and circuit-level organization of the brain.

The synapse is a highly specialized asymmetric structure that transmits and stores information in the brain. The size of pre- and postsynaptic structures and function is well coordinated at the individual synapse level. For example, large postsynaptic dendritic spines have a larger postsynaptic density with higher α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) number on their surface, while juxtaposing presynaptic terminals have a larger active zone and higher release probability. This indicates that pre- and postsynaptic domains bidirectionally communicate to coordinate assembly of specific molecules on both sides of the synaptic cleft. Cell adhesion molecules (CAMs) that localize at synapses form transsynaptic protein interactions across the synaptic cleft and play important roles in synapse formation and regulation. The extracellular domain of CAMs is essential for specific synapse formation and function. In contrast, the intracellular domain is necessary for binding with synaptic molecules and signal transduction. Therefore, CAMs play an essential role on synapse function and structure. In fact, ample evidence indicates that transsynaptic CAMs instruct and modulate functions at presynaptic sites. This chapter focuses on transsynaptic protein interactions that regulate presynaptic functions emphasizing the role of neuronal CAMs and the intracellular mechanism of their regulation.

Synaptic adhesion molecules (SAMs) are essential for driving the formation, maturation, and plasticity of synaptic connections for neural networks. MAM domain-containing glycosylphosphatidylinositol anchors (MDGAs) are a type of SAM that regulates the formation of trans-synaptic bridges, which are critical for neurotransmission and synaptic differentiation. In a recent issue of the JBC, Lee et al. uncovered that MDGA1 can control protein-protein interactions and synaptic cleft activity by adopting different global 3D conformations. This novel molecular mechanism may be applicable to other SAMs that regulate protein-protein interactions and nanoscale organization in the synaptic cleft.

The specification of synaptic properties is fundamental for the function of neuronal circuits. \"Terminal selector\" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.

Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2-3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.

Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neurexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent super-resolution nanoscopy developments have revealed that many synaptic organizers, as well as glutamate receptors and glutamate release machinery, exist as nanoclusters within synapses. However, it is unclear how such nanodomains interact with each other to organize excitatory synapses in vivo. By applying X10 expansion microscopy to epitope tag knockin mice, we found that Cbln1, Nlgn1, and LRRTM1, which share Nrxn as a common presynaptic receptor, form overlapping or separate nanodomains depending on Nrxn with or without a sequence encoded by splice site 4. The size and position of glutamate receptor nanodomains of GluD1, NMDA, and AMPA receptors were regulated by Cbln1, Nlgn1, and LRRTM1 nanodomains, respectively. These findings indicate that Nrxns anterogradely regulate the postsynaptic nanoscopic architecture of glutamate receptors through competition and coordination of Nrxn ligands.