The Interplay between Synaptic Activity and Neuroligin Function in the CNS

Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.

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Dopamine modulates the integrity of the perisynaptic extracellular matrix at excitatory synapses

10.1101/722454 ◽

2019 ◽

Cited By ~ 2

Author(s):

Jessica Mitlöhner ◽

Rahul Kaushik ◽

Hartmut Niekisch ◽

Armand Blondiaux ◽

Christine E. Gee ◽

...

Keyword(s):

Extracellular Matrix ◽

Cortical Neurons ◽

Receptor Activation ◽

Synaptic Activity ◽

Excitatory Synapses ◽

Intracellular Calcium Signaling ◽

Rat Cortical Neurons ◽

Synaptic Receptors

SummaryIn the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

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Neuromodulation of excitatory synaptogenesis in striatal development

eLife ◽

10.7554/elife.10111 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 22

Author(s):

Yevgenia Kozorovitskiy ◽

Rui Peixoto ◽

Wengang Wang ◽

Arpiar Saunders ◽

Bernardo L Sabatini

Keyword(s):

Developmental Plasticity ◽

Synapse Formation ◽

Glutamate Release ◽

Projection Neurons ◽

Excitatory Synapses ◽

Indirect Pathway ◽

Protein Receptors ◽

In Vivo Effects

Dopamine is released in the striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors.

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Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish

Genes ◽

10.3390/genes11111376 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1376

Author(s):

Alba Pensado-López ◽

Sara Veiga-Rúa ◽

Ángel Carracedo ◽

Catarina Allegue ◽

Laura Sánchez

Keyword(s):

Autism Spectrum Disorders ◽

Autism Spectrum ◽

Experimental Models ◽

Repetitive Behaviors ◽

Restricted Interests ◽

Complex Disorder ◽

Spectrum Disorders ◽

Associated Risk Factors

Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.

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The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice

10.1101/260083 ◽

2018 ◽

Cited By ~ 3

Author(s):

Da-li Tong ◽

Rui-guo Chen ◽

Yu-lan Lu ◽

Wei-ke Li ◽

Yue-fang Zhang ◽

...

Keyword(s):

Critical Role ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Inhibitory Synapses ◽

Scaffolding Proteins ◽

Loss Of Function ◽

Chinese Han

AbstractAccumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that Cntnap3-null mice exhibited deficits in social interaction, spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing the mechanistic insights for ASD.

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Differential vesicular sorting of AMPA and GABAA receptors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525726113 ◽

2016 ◽

Vol 113 (7) ◽

pp. E922-E931 ◽

Cited By ~ 33

Author(s):

Yi Gu ◽

Shu-Ling Chiu ◽

Bian Liu ◽

Pei-Hsun Wu ◽

Michael Delannoy ◽

...

Keyword(s):

Dendritic Spines ◽

Ampa Receptors ◽

Gabaa Receptors ◽

Molecular Mechanisms ◽

Inhibitory Synapses ◽

Excitatory Synapses ◽

Rab Gtpases ◽

Mature Neurons

In mature neurons AMPA receptors cluster at excitatory synapses primarily on dendritic spines, whereas GABAA receptors cluster at inhibitory synapses mainly on the soma and dendritic shafts. The molecular mechanisms underlying the precise sorting of these receptors remain unclear. By directly studying the constitutive exocytic vesicles of AMPA and GABAA receptors in vitro and in vivo, we demonstrate that they are initially sorted into different vesicles in the Golgi apparatus and inserted into distinct domains of the plasma membrane. These insertions are dependent on distinct Rab GTPases and SNARE complexes. The insertion of AMPA receptors requires SNAP25–syntaxin1A/B–VAMP2 complexes, whereas insertion of GABAA receptors relies on SNAP23–syntaxin1A/B–VAMP2 complexes. These SNARE complexes affect surface targeting of AMPA or GABAA receptors and synaptic transmission. Our studies reveal vesicular sorting mechanisms controlling the constitutive exocytosis of AMPA and GABAA receptors, which are critical for the regulation of excitatory and inhibitory responses in neurons.

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Analyses of the Autism-associated Neuroligin-3 R451C Mutation in Human Neurons Reveals a Gain-of-Function Synaptic Mechanism

10.1101/2021.12.07.471501 ◽

2021 ◽

Author(s):

Le Wang ◽

Vincent R. Mirabella ◽

Rujia Dai ◽

Xiao Su ◽

Ranjie Xu ◽

...

Keyword(s):

Gene Networks ◽

Autism Spectrum ◽

Inhibitory Synapses ◽

Excitatory Synapses ◽

Gain Of Function ◽

Protein Levels ◽

Excitatory Transmission ◽

Human Neurons ◽

The Impact

Mutations in many synaptic genes are associated with autism spectrum disorders (ASDs), suggesting that synaptic dysfunction is a key driver of ASD pathogenesis. Among these mutations, the R451C-substitution in the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs. In mice, the corresponding Nlgn3 R451C-knockin mutation recapitulates social interaction deficits of ASD patients and produces synaptic abnormalities, but the impact of the NLGN3 R451C-mutation on human neurons has not been investigated. Here, we generated human knock-in neurons with the NLGN3 R451C-mutation. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C-mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses. No significant cell death and endoplasmic reticulum stress were detected. Importantly, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into mouse forebrain. Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons that corresponded to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders. Our findings suggest that the NLGN3 R451C-mutation induces a gain-of-function enhancement in excitatory synaptic transmission that may contribute to the pathophysiology of ASDs.

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Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

10.1101/2020.09.11.294397 ◽

2020 ◽

Author(s):

Jordan J. Shimell ◽

Andrea Globa ◽

Marja D. Sepers ◽

Angela R. Wild ◽

Nusrat Matin ◽

...

Keyword(s):

Inhibitory Synapses ◽

Excitatory Synapses ◽

Silent Synapses ◽

Synapse Plasticity ◽

Hippocampal Synapses ◽

The Brain ◽

Spine Number

ABSTRACTPalmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5’s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

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Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.597812 ◽

2021 ◽

Vol 14 ◽

Author(s):

Dan Xia ◽

Li Li ◽

Binrang Yang ◽

Qiang Zhou

Keyword(s):

Valproic Acid ◽

Autism Spectrum Disorders ◽

Prefrontal Cortex ◽

Autism Spectrum ◽

Inhibitory Neurons ◽

Perineuronal Nets ◽

Spectrum Disorders ◽

Reduced Density ◽

The Relationship

Altered function or presence of inhibitory neurons is documented in autism spectrum disorders (ASD), but the mechanism underlying this alternation is poorly understood. One major subtype of inhibitory neurons altered is the parvalbumin (PV)-containing neurons with reduced density and intensity in ASD patients and model mice. A subpopulation of PV+ neurons expresses perineuronal nets (PNN). To better understand whether the relationship between PV and PNN is altered in ASD, we measured quantitatively the intensities of PV and PNN in single PV+ neurons in the prelimbic prefrontal cortex (PrL-PFC) of a valproic acid (VPA) model of ASD at different ages. We found a decreased PV intensity but increased PNN intensity in VPA mice. The relationship between PV and PNN intensities is altered in VPA mice, likely due to an “abnormal” subpopulation of neurons with an altered PV-PNN relationship. Furthermore, reducing PNN level using in vivo injection of chondroitinase ABC corrects the PV expression in adult VPA mice. We suggest that the interaction between PV and PNN is disrupted in PV+ neurons in VPA mice which may contribute to the pathology in ASD.

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Regulation of hippocampal excitatory synapses by the Zdhhc5 palmitoyl acyl transferase

Journal of Cell Science ◽

10.1242/jcs.254276 ◽

2021 ◽

Author(s):

Jordan J. Shimell ◽

Andrea Globa ◽

Marja D. Sepers ◽

Angela R. Wild ◽

Nusrat Matin ◽

...

Keyword(s):

Inhibitory Synapses ◽

Excitatory Synapses ◽

Silent Synapses ◽

Synapse Plasticity ◽

Hippocampal Synapses ◽

The Brain ◽

Spine Number

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5's enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

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Neurobiology of Autism Spectrum Disorders

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.199 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S45-S46

Author(s):

T.M. Sheldrick-Michel ◽

B.T. Morten ◽

B. Niels ◽

I. Mirolyuba

Keyword(s):

Autism Spectrum Disorders ◽

High Throughput Screening ◽

Drug Testing ◽

Developmental Stages ◽

Disease Model ◽

Behavioral Flexibility ◽

Autism Spectrum ◽

Spectrum Disorders

Autism Spectrum Disorders (ASD) is a group of neurodevelopmental disorders with heterogeneous etiology characterized by deficits in social cognition, communication, and behavioral flexibility. Disturbances on molecular and cellular level in early brain development incl. intercellular communication, an unbalanced ratio between certain neuronal populations and maturation/differentiation process, oxidative stress, happening in embryonal stages, might be promising candidates to explain the development of autistic symptoms.In order to get a deeper understanding of these processes, valid “disease models” are pivotal. A new cutting edge technique, named brain organoids, has been highlighted as a promising candidate for obtaining a better “disease model”.Brain organoids derived from patients induced pluripotent stem cells (iPSC) follow in vivo timeline development; they also have the ability to recreate the right complexity of the brains, developmental stages. On the cellular and gene expression level, organoids demonstrate a high similarity to the developing brain in vivo and can therefore recapitulate early stages of the neurogenesis. To date organoids are the most relevant cellular in vitro platform for the understanding of the mechanisms behind ADS pathology. Investigations of “mini brains” at different time points in their development will give a wider and more detailed picture of the disease dynamic and thus the development of therapeutic and prevention strategies. It is a tool that can be used for effective high throughput screening of chemical compounds as potential drugs (“in sphero” drug testing). Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors declare that they have no competing interest.

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