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 Calsyntenin-3 interacts with both α- and β-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways

2020 ◽  
Vol 295 (27) ◽  
pp. 9244-9262 ◽  
Author(s):  
Hyeonho Kim ◽  
Dongwook Kim ◽  
Jinhu Kim ◽  
Hee-Yoon Lee ◽  
Dongseok Park ◽  
...  
Keyword(s):  
Neural Circuits ◽  
Conditional Knockout ◽  
Stratum Radiatum ◽  
Excitatory Synapses ◽  
Schaffer Collateral ◽  
Ca1 Neurons ◽  
Electrophysiological Recordings ◽  
Presynaptic Differentiation ◽  
Collateral Pathways

Calsyntenin-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, using LC–MS/MS–based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, 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. 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, including Schaffer collateral afferents.

scholarly journals Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

2020 ◽  
Vol 118 (1) ◽  
pp. e2020810118
Author(s):  
Ye Wang ◽  
Wing-Yu Fu ◽  
Kit Cheung ◽  
Kwok-Wang Hung ◽  
Congping Chen ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Hippocampal Slices ◽  
Memory Formation ◽  
Conditional Knockout ◽  
Acute Administration ◽  
Excitatory Synapses ◽  
Homeostatic Synaptic Plasticity ◽  
Hippocampal Ca1

Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

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 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.

scholarly journals Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

2017 ◽  
Vol 114 (33) ◽  
pp. E6992-E7001 ◽  
Author(s):  
Huiqian Huang ◽  
Xiaochen Lin ◽  
Zhuoyi Liang ◽  
Teng Zhao ◽  
Shengwang Du ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Excitatory Synapses ◽  
Synapse Development ◽  
Synaptic Localization ◽  
Superresolution Imaging ◽  
Functional Maturation ◽  
Dendritic Spine Morphology ◽  
Brain Circuitry ◽  
Activity Dependent

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.

scholarly journals Emergence of synaptic organization and computation in dendrites

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jan H. Kirchner ◽  
Julijana Gjorgjieva
Keyword(s):  
Neural Circuits ◽  
Spatial Scales ◽  
Theoretical Research ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synaptic Organization ◽  
Synaptic Inputs ◽  
Multiple Spatial Scales ◽  
Neural Computations ◽  
The Brain

Abstract Single neurons in the brain exhibit astounding computational capabilities, which gradually emerge throughout development and enable them to become integrated into complex neural circuits. These capabilities derive in part from the precise arrangement of synaptic inputs on the neurons’ dendrites. While the full computational benefits of this arrangement are still unknown, a picture emerges in which synapses organize according to their functional properties across multiple spatial scales. In particular, on the local scale (tens of microns), excitatory synaptic inputs tend to form clusters according to their functional similarity, whereas on the scale of individual dendrites or the entire tree, synaptic inputs exhibit dendritic maps where excitatory synapse function varies smoothly with location on the tree. The development of this organization is supported by inhibitory synapses, which are carefully interleaved with excitatory synapses and can flexibly modulate activity and plasticity of excitatory synapses. Here, we summarize recent experimental and theoretical research on the developmental emergence of this synaptic organization and its impact on neural computations.

scholarly journals Presynaptic PTPσ organizes neurotransmitter release machinery at excitatory synapses

2020 ◽  
Author(s):  
Kyung Ah Han ◽  
Hee-Yoon Lee ◽  
Dongseok Lim ◽  
Jungsu Shin ◽  
Taek Han Yoon ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Conditional Knockout ◽  
Excitatory Synapses ◽  
Conditional Deletion ◽  
Evolutionarily Conserved ◽  
Bona Fide ◽  
Receptor Tyrosine Phosphatases ◽  
Postsynaptic Target

AbstractLeukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. This study systematically analyzed the effects of genetic deletions of LAR-RPTP genes by generating single conditional knockout (cKO) mice targeting PTPσ and PTPδ. Although the numbers of synapses were reduced in cultured neurons deficient in individual PTPs, abnormalities in synaptic transmission, synaptic ultrastructures, and vesicle localization were observed only in PTPσ-deficient neurons. Strikingly, loss of presynaptic PTPσ reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. However, postsynaptic PTPσ deletion had no effect on excitatory synaptic strength. Furthermore, conditional deletion of PTPσ in ventral CA1 specifically altered anxiety-like behaviors. Taken together, these results demonstrate that PTPσ is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.

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 Synaptic diversity naturally arises from neural decoding of heterogeneous populations

2021 ◽  
Author(s):  
Jacob L. Yates ◽  
Benjamin Scholl
Keyword(s):  
Dendritic Spines ◽  
Cortical Neurons ◽  
In Silico ◽  
Excitatory Synapses ◽  
Neural Decoding ◽  
Functional Heterogeneity ◽  
Synaptic Inputs ◽  
Population Codes ◽  
Optimal Decoding

Abstract The synaptic inputs to single cortical neurons exhibit substantial diversity in their sensory-driven activity. What this diversity reflects is unclear, and appears counter-productive in generating selective somatic responses to specific stimuli. We propose that synaptic diversity arises because neurons decode information from upstream populations. Focusing on a single sensory variable, orientation, we construct a probabilistic decoder that estimates the stimulus orientation from the responses of a realistic, hypothetical input population of neurons. We provide a straightforward mapping from the decoder weights to real excitatory synapses, and find that optimal decoding requires diverse input weights. Analytically derived weights exhibit diversity whenever upstream input populations consist of noisy, correlated, and heterogeneous neurons, as is typically found in vivo. In fact, in silico weight diversity was necessary to accurately decode orientation and matched the functional heterogeneity of dendritic spines imaged in vivo. Our results indicate that synaptic diversity is a necessary component of information transmission and reframes studies of connectivity through the lens of probabilistic population codes. These results suggest that the mapping from synaptic inputs to somatic selectivity may not be directly interpretable without considering input covariance and highlights the importance of population codes in pursuit of the cortical connectome.

scholarly journals A Gradient of Hippocampal Inputs to the Medial Mesocortex

2019 ◽  
Author(s):  
Emanuel Ferreira-Fernandes ◽  
Carolina Quintino ◽  
Miguel Remondes
Keyword(s):  
Retrosplenial Cortex ◽  
Anterior Cingulate ◽  
Stratum Radiatum ◽  
Inhibitory Input ◽  
Excitatory Synapses ◽  
Stratum Pyramidale ◽  
Bona Fide ◽  
Functional Circuitry

AbstractMemory-guided decisions depend on complex, finely tuned interactions between hippocampus and medial mesocortical regions anterior cingulate and retrosplenial cortices. The functional circuitry underlying these interactions is unclear. Using viral anatomical tracing,in vitroandin vivoelectrophysiology, and optogenetics, we show that such circuitry is characterized by a functional-anatomical gradient. While CG receives excitatory projections from dorsal-intermediate CA1 originated exclusively instratum pyramidale, retrosplenial cortex also receives inputs originating instratum radiatumandlacunosum-moleculare, including GAD+ neurons providing long-range GABAergic projections. Such hippocampal projections establishbona fidesynapses throughout cortical layers, with retrosplenial cortex densely targeted on its layer 3, around which it receives a combination of inhibitory and excitatory synapses. This gradient is reflected in the pattern of spontaneous oscillatory synchronicity found in the awake-behaving animal, compatible with the known functional similarity of hippocampus with retrosplenial cortex, which contrasts with the encoding of actions and “task-space” by cingulate cortex.HighlightsBoth MMC regions CG and RSC receive monosynaptic connections from the dorsal-intermediate CA1CG receives layer-sparse excitatory projections exclusively originated fromstratum piramidalewhereas RSC is targeted densely in superficial layers by a mixed excitatory and inhibitory input originating from all CA1strataCA1 monosynaptic projections correspond to active synapses onto distinct layers of the two MMC regionsDiverse synchrony between MMC and HIPP recordedin vivois consistent with the rostro-caudal diversity of direct HIPP-MMC connections

Sign in / Sign up

Export Citation Format

Share Document