Synapse Function Research Articles

Deletion of Neuroligins from Astrocytes Does Not Detectably Alter Synapse Numbers or Astrocyte Cytoarchitecture by Maturity.

Astrocytes perform multifarious roles in the formation, regulation, and function of synapses in the brain, but the mechanisms involved are incompletely understood. Interestingly, astrocytes abundantly express neuroligins, postsynaptic adhesion molecules that function as synaptic organizers by binding to presynaptic neurexins. Here we examined the function of neuroligins in astrocytes with a rigorous genetic approach that uses the conditional deletion of all major neuroligins ( Nlgn1-3 ) in astrocytes in vivo and complemented this approach by a genetic deletion of neuroligins in glia cells that are co-cultured with human neurons. Our results show that early postnatal deletion of neuroligins from astrocytes in vivo has no detectable effect on cortical or hippocampal synapses and does not alter the cytoarchitecture of astrocytes when evaluated in young adult mice. Moreover, deletion of astrocytic neuroligins in co-cultures of human neurons produced no detectable consequences for the formation and function of synapses. Thus, astrocytic neuroligins are unlikely to fundamentally shape synapse formation or astrocyte morphogenesis but likely perform other important roles that remain to be discovered.

Regulation of Dendrite and Dendritic Spine Formation by TCF20.

Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.

Dynamic FeOx/FeWOx nanocomposite memristor for neuromorphic and reservoir computing.

Memristors are crucial in computing due to their potential for miniaturization, energy efficiency, and rapid switching, making them particularly suited for advanced applications such as neuromorphic computing and in-memory operations. However, these tasks often require different operational modes-volatile or nonvolatile. This study introduces a forming-free Ag/FeOx/FeWOx/Pt nanocomposite memristor capable of both operational modes, achieved through compliance current (CC) adjustment and structural engineering. Volatile switching occurs at low CC levels (<500 μA), transitioning to nonvolatile at higher levels (mA). Operating at extremely low voltages (<0.2 V), this memristor exhibits excellent uniformity, data retention, and multilevel switching, making it highly suitable for high-density data storage. The memristor successfully mimics fundamental biological synapse functions, exhibiting potentiation, depression, and spike-rate dependent plasticity (SRDP). It effectively emulates transitions from short-term memory (STM) to long-term memory (LTM) by varying pulse characteristics. Leveraging its volatile switching and STM features, the memristor proves ideal for reservoir computing (RC), where it can emulate dynamic reservoirs for sequence data classification. A physical RC system, implemented using digits 0 to 9, achieved a recognition rate of 93.4% in off-chip training with a deep neural network (DNN), confirming the memristor's effectiveness. Overall, the dual-mode switching capability of the Ag/FeOx/FeWOx/Pt memristor enhances its potential for AI applications, particularly in temporal and sequential data processing.

Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms.

Neurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunc-tional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here we report tissue-specific ad-aptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But in-stead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destruc-tive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmis-sion. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.

Neurodegenerative and neurodevelopmental roles for bulk lipid transporters VPS13A and BLTP2 in movement disorders.

Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood. To determine the age-of-onset and tissue-specific roles of VPS13A and BLTP2 in movement disorder pathogenesis using Drosophila models. We generated tissue-specific knockdowns of the VPS13A ortholog ( Vps13 ) and the BLTP2 ortholog ( hobbit ) in neurons and muscles of Drosophila . We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function. Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by age- onset movement deficits and reduced lifespan, while muscle-specific loss affected only lifespan, revealing neurodegeneration and myopathy as independent comorbidities in VPS13A disease. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, while muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction (NMJ). VPS13A maintains neuronal survival, while BLTP2 orchestrates synaptic development. VPS13A function in muscle does not play a role in movement defects. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated movement disorders.

Dissecting the functional heterogeneity of glutamatergic synapses with high-throughput optical physiology.

Fluorescent reporters for glutamate release and postsynaptic Ca 2+ signaling are essential tools for quantifying synapse functional heterogeneity across neurons and circuits. However, leveraging these probes for neuroscience requires scalable experimental frameworks. Here, we devised a high-throughput approach to efficiently collect and analyze hundreds of optical recordings of glutaamate release activity at presynaptic boutons in cultured rat hippocampal neurons. Boutons exhibited remarkable functional heterogeneity and could be separated into multiple functional classes based on their iGluSnFR3 responses to single action potentials, paired stimuli, and synaptic parameters derived from mean-variance analysis. Finally, we developed a novel all-optical assay of pre- and postsynaptic glutamatergic synapse function. We deployed iGluSnFR3 with a red-shifted, postsynaptically-targeted Ca 2+ sensor, enabling direct imaging and analysis of NMDA receptor-mediated synaptic transmission at large numbers of dendritic spines. This work enables direct observation of the flow of information at single synapses and should speed detailed investigations of synaptic functional heterogeneity.

Endosomal sorting protein SNX4 limits synaptic vesicle docking and release.

Sorting nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how SNX4 affects synapse function remains unknown. We generated a conditional SNX4 knock-out mouse model and report that SNX4 cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal. SNX4 depletion did not affect vesicle recycling, basic autophagic flux, or the levels and localization of SNARE-protein VAMP2/synaptobrevin-2. However, SNX4 depletion affected synapse ultrastructure: an increase in docked synaptic vesicles at the active zone, while the overall vesicle number was normal, and a decreased active zone length. These effects together lead to a substantially increased density of docked vesicles per release site. In conclusion, SNX4 is a negative regulator of synaptic vesicle docking and release. These findings suggest a role for SNX4 in synaptic vesicle recruitment at the active zone.

The gating properties of Drosophila NMJ glutamate receptors and their dependence on Neto.

The Drosophila neuromuscular junction (NMJ) is a powerful genetic system that has revealed numerous conserved mechanisms for synapse development and homeostasis. The fly NMJ uses glutamate as the excitatory neurotransmitter and relies on kainate-type glutamate receptors and their auxiliary protein Neto for synapse assembly and function. However, despite decades of study, the reconstitution of NMJ glutamate receptors using heterologous systems has been achieved only recently, and there are no reports on the gating properties for the recombinant receptors. Here, using outside-out, patch clamp recordings and fast ligand application, we examine for the first time the biophysical properties of native type-A and type-B NMJ receptors in complexes with either Neto-α or Neto-β and compare them with recombinant receptors expressed in HEK293T cells. We found that type-A and type-B receptors have strikingly different gating properties that are further modulated by Neto-α and Neto-β. We captured single-channel events and revealed major differences between type-A and type-B receptors and also between Neto splice variants. Surprisingly, we found that deactivation is extremely fast and that the decay of synaptic currents resembles the rate of ionotropic glutamate receptor (iGluR) desensitization. The functional analyses of recombinant iGluRs that we report here should greatly facilitate the interpretation of compound in vivo phenotypes of mutant animals. KEY POINTS: We report the reconstitution of Drosophila neuromuscular junction ionotropic glutamate receptors (iGluRs) with Neto splice forms. Using outside-out patches and fast ligand application, we examine the deactivation and desensitization of the four iGluR/Neto complexes found in vivo. Expression of functional channels is absolutely dependent on Neto. Single-channel recordings revealed different lifetimes for different receptor complexes. The decay of synaptic currents is controlled by desensitization.

Uncovering the electrical synapse proteome in retinal neurons via in vivo proximity labeling.

Through decades of research, we have gained a comprehensive understanding of the protein complexes underlying function and regulation of chemical synapses in the nervous system. Despite the identification of key molecules such as ZO-1 or CaMKII, we currently lack a similar level of insight into the electrical synapse proteome. With the advancement of BioID as a tool for in vivo proteomics, it has become possible to identify complex interactomes of a given protein of interest by combining enzymatic biotinylation with subsequent streptavidin affinity capture. In the present study, we applied different BioID strategies to screen the interactomes of Connexin 36 (mouse) the major neuronal connexin and its zebrafish orthologue Cx35b in retinal neurons. For in vivo proximity labeling in mice, we took advantage of the Cx36-EGFP strain and expressed a GFP-nanobody-TurboID fusion construct selectively in AII amacrine cells. For in vivo BioID in zebrafish, we generated a transgenic line expressing a Cx35b-TurboID fusion under control of the Cx35b promoter. Both two strategies allowed us to capture a plethora of molecules that were associated with electrical synapses and showed a high degree of evolutionary conservation in the proteomes of both species. Besides known interactors of Cx36 such as ZO-1 and ZO-2 we have identified more than 50 new proteins, such as scaffold proteins, adhesion molecules and regulators of the cytoskeleton. We further determined the subcellular localization of these proteins in AII amacrine and tested potential binding interactions with Cx36. Of note, we identified signal induced proliferation associated 1 like 3 (SIPA1L3), a protein that has been implicated in cell junction formation and cell polarity as a new scaffold of electrical synapses. Interestingly, SIPA1L3 was able to interact with ZO-1, ZO-2 and Cx36, suggesting a pivotal role in electrical synapse function. In summary, our study provides a first detailed view of the electrical synapse proteome in retinal neurons.

Electrical synapse molecular diversity revealed by proximity-based proteomic discovery.

Neuronal circuits are composed of synapses that are either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through interneuronal gap junction channels. While the molecular complexity that controls chemical synapse structure and function is well appreciated, the proteins of electrical synapses beyond the gap-junction-forming Connexins are not well defined. Yet, electrical synapses are expected to be molecularly complex beyond the gap junctions. Connexins are integral membrane proteins requiring vesicular transport and membrane insertion/retrieval to achieve function, homeostasis, and plasticity. Additionally, electron microscopy of neuronal gap junctions reveals neighboring electron dense regions termed the electrical synapse density (ESD). To reveal the molecular complexity of the electrical synapse proteome, we used proximity-dependent biotinylation (TurboID) linked to neural Connexins in zebrafish. Proteomic analysis of developing and mature nervous systems identifies hundreds of Connexin-associated proteins, with overlapping and distinct representation during development and adulthood. The identified protein classes span cell adhesion molecules, cytoplasmic scaffolds, vesicular trafficking, and proteins usually associated with the post synaptic density (PSD) of chemical synapses. Using circuits with stereotyped electrical and chemical synapses, we define molecular sub-synaptic compartments of ESD localizing proteins, we find molecular heterogeneity amongst electrical synapse populations, and we examine the synaptic intermingling of electrical and chemical synapse proteins. Taken together, these results reveal a new complexity of electrical synapse molecular diversity and highlight a novel overlap between chemical and electrical synapse proteomes. Moreover, human homologs of the electrical synapse proteins are associated with autism, epilepsy, and other neurological disorders, providing a novel framework towards understanding neuro-atypical states.

A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning.

Spinocerebellar ataxia type 22 (SCA22) caused by KCND3 mutations is an autosomal dominant disorder. We established a mouse model carrying the Kcnd3 F227del mutation to study the molecular pathogenesis. Four findings were pinpointed. First, the heterozygous mice exhibited an early onset of defects in motor coordination and balance which mirror those of SCA22 patients. The degeneration and a minor loss of Purkinje cells, together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the Kcnd3 F227del mutant protein. Second, the mutant protein is retained by the endoplasmic reticulum and Golgi, leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage of the Golgi is the earliest manifestation. Third, analysis of the transcriptome revealed that the Kcnd3 F227del mutation down-regulates a panel of genes involved in the functioning of synapses and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes were detectable in knockout mice carrying a loss-of-function Kcnd3 mutation. Thus, Kcnd3 F227del is a dominant-negative mutation. This mouse model may serve as a preclinical model for exploring therapeutic strategies to treat patients. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Enhancement of Synaptic Behavior in Organic Electrochemical Transistors via the Introduction of Layer‐by‐Layer Grown Metal‐Organic Framework

AbstractOrganic electrochemical transistors (OECTs) are promising for neuromorphic architectures as they can generate multiple electrical states through the control of ion transport. However, conventional OECTs face limitations in mimicking a fully functional biological synapse due to their inability to achieve long‐term plasticity. In this study, a metal‐organic framework (MOF)‐enhanced OECT (MOECT) is fabricated by introducing MOF into the ion‐organic semiconductor (OSC) layer. MOFs are synthesized using the layer‐by‐layer (LBL) method, and additional cross‐linked OSC is introduced to prevent damage to the semiconductor layers during synthesis. The synthesized MOF layers hinder the rediffusion of ions in OECT, allowing ions to remain in the OSC for an extended period. In this study, the MOECT showed a change in current depending on the doping level, recording a current state 4.4 × 107 times higher than that of pristine OECT. Ultimately, the developed MOECTs are applied as synaptic transistors. MOECTs show 14% higher excitatory postsynaptic current (EPSC) after 130 s compared to pristine OECT, thereby strengthening the long‐term plasticity characteristics of neuromorphic devices. This method enhances the performance of synaptic transistors by introducing MOF, offering various possibilities through the selection of different MOF structures and ions, indicating it is a methodological approach with high potential.

Acute introduction of monomeric or multimeric α-synuclein induces distinct impacts on synaptic vesicle trafficking at lamprey giant synapses.

Synaptic aggregation of α-synuclein often occurs in Parkinson's disease (PD), dementia with Lewy bodies (DLB) and other synucleinopathies and is associated with cognitive deficits and dementia. Thus, it is important to understand how accumulation of α-synuclein affects synapse structure and function. Native, physiological α-synuclein comprises a mixture of tetramers and related physiological oligomers (60-100kDa) in equilibrium with monomeric α-synuclein. We previously demonstrated that acutely increasing the levels of physiologicalα-synuclein impaired intracellular synaptic vesicle trafficking and produced a pleiotropic phenotype, raising questions about which aspects of the synaptic phenotype were due to multimeric versus monomeric α-synuclein. Here, we address this by taking advantage of the unique features of the lamprey giant reticulospinal (RS) synapse, a vertebrate synapse that is amenable to acute perturbations of presynaptic processes via microinjection of purified proteins. α-Synuclein monomers and multimers were purified from HEK cells and separately introduced to lamprey synapses. Ultrastructural analysis revealed that both multimeric and monomeric α-synuclein impaired intracellular vesicle trafficking, leading to a loss of synaptic vesicles and buildup of endosomes. However, while monomeric α-synuclein additionally induced atypical fusion/fission at the active zone and impaired clathrin-mediated endocytosis, multimeric α-synuclein did not. Conversely, multimeric α-synuclein led to a decrease in synaptic vesicle docking, which was not observed with monomeric α-synuclein. These data provide further evidence that different molecular species of α-synuclein produce distinct and complex impacts on synaptic vesicle trafficking and reveal important insights into the cell biological processes that are affected in PD and DLB. KEY POINTS: α-Synuclein accumulation at synapses is associated with cognitive decline and dementia in Parkinson's disease and other synucleinopathies. We previously showed that acute introduction of excess human brain-derived α-synuclein to lamprey giant synapses caused pleiotropic phenotypes on synaptic vesicle trafficking, probably due to the mixture of molecular species of α-synuclein. Here, we dissected which aspects of the synaptic phenotypes were caused by monomeric (14kDa) or multimeric (60-100kDa) α-synuclein by purifying each molecular species and introducing each one separately to synapses via axonal microinjection. While monomeric α-synuclein inhibited clathrin-mediated synaptic vesicle endocytosis, multimeric α-synuclein primarily impaired endosomal trafficking. These findings reveal that different molecular species of α-synuclein have distinct impacts on synapses, suggesting different cellular and molecular targets.

Bioinformatic analysis constructs an optimal prognostic index for survival-related variables (OPISV) based on whole-genome expression data in Glioblastoma

PurposeUsing clinical information and transcriptomic sequencing data from glioblastoma (GBM) patients in the TCGA database to perform gene-by-gene analysis that is aligned with individual patient characteristics and develop an optimal prognostic index of survival-related variables (OPISV) through iterative machine learning techniques to predict the prognosis of GBM patients. Study designThe TCGA dataset was utilized as the training dataset, while two GEO datasets served as independent validation cohorts. Initially, survival analysis (p < 0.001***), differential gene expression analysis (p < 0.05*), and univariate Cox regression analysis (p < 0.05*) were employed to identify genes that are highly correlated with patient prognosis and exhibit significant differences in survival status. Subsequently, incorporating the non-excludable variable of age, a multivariate Cox regression analysis was performed in a stepwise manner to construct the OPISV. Finally, logistic and LASSO regressions were used to validate the association between the identified genes and patient survival. The OPISV performance is evaluated and its potential mechanisms are explored. ResultsAge, CTSD, PTPRN, PTPRN2, NSUN5, DNAJC30 and SOX21 emerged as the optimal variables through multivariate Cox regression iterations. Further analysis characterized Age, PTPRN and DNAJC30 as independent prognostic risk factors for constructing OPISV, which is validated with external GEO datasets and GEPIA database. In OPISV_high populations, significantly upregulated GABAergic synapse function was exposed. Differential genes identified from gene clustering of the GABAergic synapse pathway and gene module highly correlated with GABAergic synapse in the WGCNA analysis are pointing unequivocally to the glioma progress. ConclusionOPISV is feasible for predicting patient survival, as it may serve as a potential mechanism underlying the involvement of GABAergic synapses in the progression of GBM.

Zinc signaling controls astrocyte-dependent synapse modulation via the PAF receptor pathway.

Astrocytes are important regulators of neuronal development and activity. Their activation plays a key role in the response to many central nervous system (CNS) pathologies. However, reactive astrocytes are a double-edged sword as their chronic or excessive activation may negatively impact CNS physiology, for example, via abnormal modulation of synaptogenesis and synapse function. Accordingly, astrocyte activation has been linked to neurodegenerative and neurodevelopmental disorders. Therefore, the attenuation of astrocyte activation may be an important approach for preventing and treating these disorders. Since zinc deficiency has been consistently linked to increased pro-inflammatory signaling, we aimed to identify cellular zinc-dependent signaling pathways that may lead to astrocyte activation using techniques such as immunocytochemistry and protein biochemistry to detect astrocyte GFAP expression, fluorescent imaging to detect oxidative stress levels in activated astrocytes, cytokine profiling, and analysis of primary neurons subjected to astrocyte secretomes. Our results reveal a so far not well-described pathway in astrocytes, the platelet activation factor receptor (PAFR) pathway, as a critical zinc-dependent signaling pathway that is sufficient to control astrocyte reactivity. Low zinc levels activate PAFR signaling-driven crosstalk between astrocytes and neurons, which alters excitatory synapse formation during development in a PAFR-dependent manner. We conclude that zinc is a crucial signaling ion involved in astrocyte activation and an important dietary factor that controls astrocytic pro-inflammatory processes. Thus, targeting zinc homeostasis may be an important approach in several neuroinflammatory conditions.

The Alzheimer's Disease Risk Gene CD2AP Functions in Dendritic Spines by Remodeling F-Actin.

CD2-associated protein (CD2AP) was identified as a genetic risk factor for late-onset Alzheimer's disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases β-amyloid (Aβ) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Postsynaptic reexpression of CD2AP, but not blocking Aβ production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics.

Loss of TET Activity in the Postnatal Mouse Brain Perturbs Synaptic Gene Expression and Impairs Cognitive Function.

Conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins leads to the accumulation of 5hmC in the central nervous system; however, the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive. We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons. These mice exhibit significantly reduced 5hmC levels, altered dendritic spine morphology within brain regions crucial for cognition, and substantially impaired spatial and associative memories. Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes, which display changes in both 5hmC/5mC levels and expression patterns, are involved in synapse-related functions. Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.

LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

Synapses are organized into nanocolumns that control synaptic transmission efficacy through precise alignment of postsynaptic neurotransmitter receptors and presynaptic release sites. Recent evidence show that Leucine-Rich Repeat Transmembrane protein LRRTM2, highly enriched and confined at synapses, interacts with Neurexins through its C-terminal cap, but the role of this binding interface has not been explored in synapse formation and function. Here, we develop a conditional knock-out mouse model (cKO) to address the molecular mechanisms of LRRTM2 regulation, and its role in synapse organization and function. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function in mice. Surface expression, synaptic clustering, and membrane dynamics of LRRTM2 are tightly controlled by selective motifs in the C-terminal domain. Conversely, the N-terminal domain controls presynapse nano-organization and postsynapse AMPAR sub-positioning and stabilization through the recently identified Neurexin-binding interface. Thus, we identify LRRTM2 as a central organizer of pre- and post- excitatory synapse nanostructure through interaction with presynaptic Neurexins.

Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice.

Genetic variants in TRIO are associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associated Trio variants - +/K1431M (ASD), +/K1918X (SCZ), and +/M2145T (bipolar disorder, BPD) - impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. Trio variants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in +/K1431M and +/M2145T cortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but +/K1431M mice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in +/K1431M variant cortex. Our work reveals that discrete NDD-associated Trio variants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.

All-In-One Optoelectronic Transistors for Bio-Inspired Visual System.

Visual perception has profound effects on human decision-making and emotional responses. Replicating the functions of the human visual system through device development has been a constant pursuit in recent years. However, to fully simulate the various functions of the human visual system, it is often necessary to integrate multiple devices with different functions, resulting in complex, large-volume device structures and increased power consumption. Here, an optoelectronic transistor with comprehensive visual functions is introduced. By coupling diverse photoreceptive properties of the channel and electrical regulation through charge injection/ferroelectric switching from the hafnium-based gate, the devices can simulate functions of both photoreceptors in the retina and synapses in the visual cortex. A device array is constructed to confirm the perceptual functions of cone and rod cells. Subsequently, color discrimination and recognition for color images are achieved by combining the tunable perception and synapse functions. Then an intelligent traffic judgment system with this all-in-one device is developed, which is capable of making judgments and decisions regarding traffic signals and pedestrian movements. This work provides a potential solution for developing compact and efficient devices for the next-generation bio-inspired visual system.