scholarly journals Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development

2013 ◽  
Vol 200 (3) ◽  
pp. 321-336 ◽  
Author(s):  
Katherine L. Pettem ◽  
Daisaku Yokomaku ◽  
Hideto Takahashi ◽  
Yuan Ge ◽  
Ann Marie Craig
Keyword(s):  
Neurodevelopmental Disorders ◽  
Hippocampal Neurons ◽  
Rare Variants ◽  
Inhibitory Synapse ◽  
Excitatory Synapse ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synapse Development ◽  
Multiple Protein ◽  
Synapse Density

Rare variants in MDGAs (MAM domain–containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse–organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin–neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.

Electrophysiological evidence from glutamate microapplications for local excitatory circuits in the CA1 area of rat hippocampal slices

1988 ◽  
Vol 59 (1) ◽  
pp. 110-123 ◽  
Author(s):  
E. P. Christian ◽  
F. E. Dudek
Keyword(s):  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Recording Site ◽  
Postsynaptic Potentials ◽  
Inhibitory Postsynaptic Potentials ◽  
Ca1 Area ◽  
Transverse Slice

1. Evidence for local excitatory synaptic connections in CA1 of the rat hippocampus was obtained by recording excitatory postsynaptic potentials (EPSPs) intracellularly from pyramidal cells during local microapplications of glutamate. 2. Experiments were performed in hippocampal slices cut parallel to (transverse slice) or perpendicular to (longitudinal slice) alvear fibers. In normal solutions, glutamate microdrops (10–20 mM, 10–20 micron diam) applied in CA1 within 400 micron of recorded cells sometimes increased the frequency of inhibitory postsynaptic potentials for 5–10 s in both transverse and longitudinal slices. Increases in EPSP frequency were also occasionally observed, but only in transverse slices. Tetrodotoxin (1 microgram/ml) blocked glutamate-induced increases in PSP frequency, thus indicating that they were not caused by subthreshold effects on presynaptic terminals. Increases in PSP frequency were interpreted to result from glutamate activation of hippocampal neurons with inhibitory and excitatory connections to recorded neurons. 3. In both slice orientations, local excitatory circuits were studied in more isolated conditions by surgically separating CA1 from CA3 (transverse slices) and by blocking GABAergic inhibitory synapses with picrotoxin (5–10 microM). Microdrops were systematically applied at 200 and 400 micron on each side of the recording site. Significant glutamate-induced increases in EPSP frequency were observed in neurons from both slice orientations to microdrops in at least one of the locations. This provided evidence that excitatory synapses are present in both transverse and longitudinal slices. 4. Substantial increases in EPSP frequency only occurred in neurons from longitudinal slices when glutamate was microapplied 200 micron or less from the recording site. In transverse slices, however, large increases in EPSP frequency were observed to glutamate microapplications at 200 or 400 micron. These data suggest that CA1 local excitatory connections project for longer distances in the transverse than in the longitudinal plane of section. 5. Increases in EPSP frequency, averaged across cells, did not differ significantly in the four microapplication sites in either transverse or longitudinal slices. Thus local excitation in CA1 does not appear to be asymmetrically arranged in the way suggested for CA3. 6. The densities of local excitatory circuits in CA1 versus CA3 were studied by quantitatively comparing glutamate-induced increases in EPSP frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyung Ah Han ◽  
Jinhu Kim ◽  
Hyeonho Kim ◽  
Dongwook Kim ◽  
Dongseok Lim ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Pdz Domain ◽  
Protein Tyrosine Phosphatases ◽  
Excitatory Synapse ◽  
Receptor Protein ◽  
Binding Motif ◽  
Synapse Development

AbstractMembers of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.

scholarly journals Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons

2011 ◽  
Vol 194 (2) ◽  
pp. 323-334 ◽  
Author(s):  
Jaewon Ko ◽  
Gilberto J. Soler-Llavina ◽  
Marc V. Fuccillo ◽  
Robert C. Malenka ◽  
Thomas C. Südhof
Keyword(s):  
Hippocampal Neurons ◽  
Transmembrane Proteins ◽  
Synaptic Activity ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synapse Elimination ◽  
Synapse Loss ◽  
A Cell ◽  
Dependent Signaling Pathway ◽  
Cultured Hippocampal Neurons

Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway.

scholarly journals Trophic Factor-Induced Plasticity of Synaptic Connections Between Identified Lymnaea Neurons

1999 ◽  
Vol 6 (3) ◽  
pp. 307-316 ◽  
Author(s):  
Melanie A. Woodin ◽  
Toshiro Hamakawa ◽  
Mayumi Takasaki ◽  
Ken Lukowiak ◽  
Naweed I. Syed
Keyword(s):  
Tyrosine Kinases ◽  
Synapse Formation ◽  
Initial Period ◽  
Defined Medium ◽  
Inhibitory Synapse ◽  
Trophic Factors ◽  
Trophic Factor ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synaptic Connections

Neurotrophic factors participate in both developmental and adult synaptic plasticity; however, the underlying mechanisms remain unknown. Using soma–soma synapses between the identified Lymnaea neurons, we demonstrate that the brain conditioned medium (CM)-derived trophic factors are required for the formation of excitatory but not the inhibitory synapse. Specifically, identified presynaptic [right pedal dorsal 1 (RPeD1) and visceral dorsal 4 (VD4)] and postsynaptic [visceral dorsal 2/3 (VD2/3) and left pedal dorsal 1 (LPeD1)] neurons were soma–soma paired either in the absence or presence of CM. We show that in defined medium (DM—does not contain extrinsic trophic factors), appropriate excitatory synapses failed to develop between RPeD1 and VD2/3. Instead, inappropriate inhibitory synapses formed between VD2/3 and RPeD1. Similarly, mutual inhibitory synapses developed between VD4 and LPeD1 in DM. These inhibitory synapses were termed novel because they do not exist in the intact brain. To test whether DM-induced, inappropriate inhibitory synapses could be corrected by the addition of CM, cells were first paired in DM for an initial period of 12 hr. DM was then replaced with CM, and simultaneous intracellular recordings were made from paired cells after 6–12 hr of CM substitution. Not only did CM induce the formation of appropriate excitatory synapses between both cell pairs, but it also reduced the incidence of inappropriate inhibitory synapse formation. The CM-induced plasticity of synaptic connections involved new protein synthesis and transcription and was mediated via receptor tyrosine kinases. Taken together, our data provide the first direct insight into the cellular mechanism underlying trophic factor-induced specificity and plasticity of synaptic connections between soma–soma paired Lymnaea neurons.

scholarly journals Inhibitory control in neuronal networks relies on the extracellular matrix integrity

2021 ◽  
Author(s):  
Egor Dzyubenko ◽  
Michael Fleischer ◽  
Daniel Manrique-Castano ◽  
Mina Borbor ◽  
Christoph Kleinschnitz ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Inhibitory Control ◽  
Neuronal Networks ◽  
Synaptic Strength ◽  
Inhibitory Synapse ◽  
Receptor Expression ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Neuronal Network Activity ◽  
Synapse Density

AbstractInhibitory control is essential for the regulation of neuronal network activity, where excitatory and inhibitory synapses can act synergistically, reciprocally, and antagonistically. Sustained excitation-inhibition (E-I) balance, therefore, relies on the orchestrated adjustment of excitatory and inhibitory synaptic strength. While growing evidence indicates that the brain’s extracellular matrix (ECM) is a crucial regulator of excitatory synapse plasticity, it remains unclear whether and how the ECM contributes to inhibitory control in neuronal networks. Here we studied the simultaneous changes in excitatory and inhibitory connectivity after ECM depletion. We demonstrate that the ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Quantification of synapses and super-resolution microscopy showed that depletion of the ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. The reduction of inhibitory synapse density is partially compensated by the homeostatically increasing synaptic strength via the reduction of presynaptic GABAB receptors, as indicated by patch-clamp measurements and GABAB receptor expression quantifications. However, both spiking and bursting activity in neuronal networks is increased after ECM depletion, as indicated by multi-electrode recordings. With computational modelling, we determined that ECM depletion reduces the inhibitory connectivity to an extent that the inhibitory synapse scaling does not fully compensate for the reduced inhibitory synapse density. Our results indicate that the brain’s ECM preserves the balanced state of neuronal networks by supporting inhibitory control via inhibitory synapse stabilization, which expands the current understanding of brain activity regulation. Graphic abstract

scholarly journals Hyaluronan regulates synapse formation and function in developing neural networks

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily Wilson ◽  
Warren Knudson ◽  
Karen Newell-Litwa
Keyword(s):  
Extracellular Matrix ◽  
Brain Development ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Inhibitory Synapse ◽  
Synaptic Function ◽  
Excitatory Synapse ◽  
Network Activity ◽  
Excitatory Synapses ◽  
Inhibitory Signaling

Abstract Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.

scholarly journals Lrfn2-mutant mice display suppressed synaptic plasticity and inhibitory synapse development and abnormal social communication and startle response

2018 ◽  
Author(s):  
Yan Li ◽  
Ryunhee Kim ◽  
Yi Sul Cho ◽  
Doyoun Kim ◽  
Kyungdeok Kim ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Social Communication ◽  
Acoustic Startle ◽  
Ultrasonic Vocalization ◽  
Inhibitory Synapse ◽  
Excitatory Synapse ◽  
Synapse Development

AbstractSALM1, also known as LRFN2, is a PSD-95-interacting synaptic adhesion molecule implicated in the regulation of NMDA receptor (NMDAR) clustering largely based on in vitro data, although its in vivo functions remain unclear. Here, we found that mice lacking SALM1/LRFN2 (Lrfn2-/- mice) show a normal density of excitatory synapses but altered excitatory synaptic function, including enhanced NMDAR-dependent synaptic transmission but suppressed NMDAR-dependent synaptic plasticity in the hippocampal CA1 region. Unexpectedly, SALM1 expression is detected in both glutamatergic and GABAergic neurons, and Lrfn2-/- CA1 pyramidal neurons show decreases in the density of inhibitory synapses and frequency of spontaneous inhibitory synaptic transmission. Behaviorally, ultrasonic vocalization was suppressed in Lrfn2-/- pups separated from their mothers, and acoustic startle was enhanced, but locomotion, anxiety-like behavior, social interaction, repetitive behaviors, and learning and memory were largely normal in adult Lrfn2-/- mice. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, and social communication and startle behaviors in mice.Significance StatementSynaptic adhesion molecules regulate synapse development and function, which govern neural circuit and brain functions. The SALM/LRFN family of synaptic adhesion proteins consists of five known members whose in vivo functions are largely unknown. Here we characterized mice lacking SALM1/LRFN2 (SALM1 knockout) known to associate with NMDA receptors and found that these mice showed altered NMDA receptor-dependent synaptic transmission and plasticity, as expected, but unexpectedly also exhibited suppressed inhibitory synapse development and synaptic transmission. Behaviorally, SALM1 knockout pups showed suppressed ultrasonic vocalization upon separation from their mothers, and SALM1 knockout adults showed enhanced responses to loud acoustic stimuli. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, social communication, and acoustic startle behavior.

scholarly journals Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

2022 ◽  
Author(s):  
K. Ulrich Bayer ◽  
Sarah G Cook ◽  
Nicole L Rumian
Keyword(s):  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Long Term Potentiation ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Dependent Protein ◽  
Regulatory Functions

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

scholarly journals Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

2020 ◽  
Author(s):  
Hyeonho Kim ◽  
Dongwook Kim ◽  
Jinhu Kim ◽  
Hee-Yoon Lee ◽  
Dongseok Park ◽  
...  
Keyword(s):  
Neural Circuits ◽  
Conditional Knockout ◽  
Excitatory Synapse ◽  
Stratum Radiatum ◽  
Excitatory Synapses ◽  
Synapse Development ◽  
Ca1 Neurons ◽  
Synaptic Inputs ◽  
Presynaptic Differentiation

AbstractCalsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, we show that β-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive β-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs, and moderate impairment of light-induced anxiety-like behaviors in mice. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits.

scholarly journals MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Adam J Harrington ◽  
Aram Raissi ◽  
Kacey Rajkovich ◽  
Stefano Berto ◽  
Jaswinder Kumar ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Neurodevelopmental Disorders ◽  
Network Activity ◽  
Excitatory Synapses ◽  
Dramatic Reduction ◽  
Excitatory Neurons ◽  
Synapse Density ◽  
A Cell ◽  
Differential Gene

Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.

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