scholarly journals Kalirin-7 is a Key Player in the Formation of Excitatory Synapses in Hippocampal Neurons

2010 ◽  
Vol 10 ◽  
pp. 1655-1666 ◽  
Author(s):  
Xin-Ming Ma
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Pdz Domain ◽  
Long Term Potentiation ◽  
Binding Motif ◽  
Excitatory Synapses ◽  
Spine Density ◽  
Chronic Cocaine ◽  
And Function

Kalirin-7 (Kal7), a major isoform of Kalirin in the adult rodent hippocampus, is exclusively localized to the postsynaptic side of mature excitatory synapses in hippocampal neurons. Kal7 interacts with multiple PDZ domain—containing proteins through its unique PDZ binding motif. Overexpression of Kal7 increases spine density and spine size, whereas reduction of endogenous Kal7 expression by small hairpin RNA (shRNA) causes a decrease in synapse number and spine density in cultured hippocampal neurons. Hippocampal CA1 pyramidal neurons of Kal7 knockout (Kal7KO) mice show decreased spine density, spine length, synapse number, and postsynaptic density (PSD) size in their apical dendrites; are deficient in long-term potentiation (LTP); and exhibit decreased frequency of spontaneous excitatory postsynaptic current (sEPSC). Kal7 plays a key role in estrogen-mediated spine/synapse formation in hippocampal neurons. Kal7 is also an essential determinant of dendritic spine formation following chronic cocaine treatment. Kal7 plays a key role in excitatory synapse formation and function.

scholarly journals Kalirin, a Key Player in Synapse Formation, Is Implicated in Human Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Prashant Mandela ◽  
Xin-Ming Ma
Keyword(s):  
Learning And Memory ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Pdz Domain ◽  
Long Term Potentiation ◽  
Human Diseases ◽  
Binding Motif ◽  
Spine Density ◽  
Morphological Alterations

Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington’s Disease, Alzheimer’s Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function.

scholarly journals Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

2019 ◽  
Vol 400 (9) ◽  
pp. 1129-1139 ◽  
Author(s):  
Iryna Hlushchenko ◽  
Pirta Hotulainen
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Signal Molecule ◽  
Brain Functions ◽  
Dendritic Shaft ◽  
Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

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 Activity-Induced Nr4a1 Regulates Spine Density and Distribution Pattern of Excitatory Synapses in Pyramidal Neurons

Neuron ◽  
2014 ◽  
Vol 83 (2) ◽  
pp. 431-443 ◽  
Author(s):  
Yelin Chen ◽  
Yuanyuan Wang ◽  
Ali Ertürk ◽  
Dara Kallop ◽  
Zhiyu Jiang ◽  
...  
Keyword(s):  
Distribution Pattern ◽  
Pyramidal Neurons ◽  
Excitatory Synapses ◽  
Spine Density

scholarly journals CREB Activation Mediates Plasticity in Cultured Hippocampal Neurons

1998 ◽  
Vol 6 (3) ◽  
pp. 1-7 ◽  
Author(s):  
Menahem Segal ◽  
Diane D. Murphy
Keyword(s):  
Cyclic Amp ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Creb Phosphorylation ◽  
Molecular Events ◽  
Term Potentiation ◽  
Element Binding Protein ◽  
Responsive Element

Activation of cyclic AMP dependent kinase is believed to mediate slow onset, long-term potentiation (LTP) in central neurons. Cyclic- AMP activates a cascade of molecular events leading to phosphorylation of the nuclear cAMP responsive element binding protein (pCREB). Whereas a variety of stimuli lead to activation of CREB, the molecular processes downstream of CREB, which may be relevant to neuronal plasticity, are yet largely unknown. We have recently found that following exposure to estradiol, pCREB mediates the large increase in dendritic spine density in cultured rat hippocampal neurons. We now extend these observations to include other stimuli, such as bicuculline, that cause the formation of new dendritic spines. Such stimuli share with estradiol the same mechanism of action in that both require activity-dependent CREB phosphorylation. Our observations suggest that CREB phosphorylation is a necessary, but perhaps not sufficient, step in the process leading to the generation of new dendritic spines and perhaps to functional plasticity as well.

scholarly journals Cx50 requires an intact PDZ-binding motif and ZO-1 for the formation of functional intercellular channels

2011 ◽  
Vol 22 (23) ◽  
pp. 4503-4512 ◽  
Author(s):  
Zhifang Chai ◽  
Daniel A. Goodenough ◽  
David L. Paul
Keyword(s):  
Gap Junction ◽  
Hela Cells ◽  
Pdz Domain ◽  
Cell Communication ◽  
Normal Function ◽  
Scaffolding Protein ◽  
Binding Motif ◽  
Interacting Protein ◽  
And Function

The three connexins expressed in the ocular lens each contain PDZ domain–binding motifs directing a physical association with the scaffolding protein ZO-1, but the significance of the interaction is unknown. We found that Cx50 with PDZ-binding motif mutations did not form gap junction plaques or induce cell–cell communication in HeLa cells, whereas the addition of a seven–amino acid PDZ-binding motif restored normal function to Cx50 lacking its entire C-terminal cytoplasmic domain. C-Terminal deletion had a similar although weaker effect on Cx46 but little if any effect on targeting and function of Cx43. Furthermore, small interfering RNA knockdown of ZO-1 completely inhibited the formation of gap junctions by wild-type Cx50 in HeLa cells. Thus both a PDZ-binding motif and ZO-1 are necessary for Cx50 intercellular channel formation in HeLa cells. Knock-in mice expressing Cx50 with a PDZ-binding motif mutation phenocopied Cx50 knockouts. Furthermore, differentiating lens fibers in the knock-in displayed extensive intracellular Cx50, whereas plaques in mature fibers contained only Cx46. Thus normal Cx50 function in vivo also requires an intact PDZ domain–binding motif. This is the first demonstration of a connexin-specific requirement for a connexin-interacting protein in gap junction assembly.

scholarly journals IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer s disease mouse model

2021 ◽  
Author(s):  
Niklas Lonnemann ◽  
Shirin Hosseini ◽  
Melanie Ohm ◽  
Karsten Hiller ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cognitive Abilities ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Chronic Neuroinflammation ◽  
Model Of Alzheimer’S Disease ◽  
Term Potentiation ◽  
Anti Inflammatory ◽  
And Function ◽  
And Behavior

The anti-inflammatory cytokine interleukin-37 (IL-37) is a member of the IL-1 family but not expressed in mice. We used a human IL 37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Those studies demonstrate an immune-modulatory role of IL-37 which can be characterized as an important suppressor of innate immunity. We investigated the functions of IL-37 in the CNS and explored the effects of IL-37 on neuronal architecture and function, microglia phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. Reduced spine density, activated microglia phenotype and impaired long-term potentiation (LTP) were observed in wild-type mice after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer's disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent the loss of cognitive abilities in a mouse model of AD.

scholarly journals Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Silvia Ripamonti ◽  
Mateusz C Ambrozkiewicz ◽  
Francesca Guzzi ◽  
Marta Gravati ◽  
Gerardo Biella ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Hippocampal Pyramidal Neurons ◽  
Excitatory Transmission ◽  
Oxytocin Receptors ◽  
Synapse Density ◽  
Protein Components ◽  
And Function

Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances.

scholarly journals SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis

2008 ◽  
Vol 182 (1) ◽  
pp. 141-155 ◽  
Author(s):  
Hsu-Wen Chao ◽  
Chen-Jei Hong ◽  
Tzyy-Nan Huang ◽  
Yi-Ling Lin ◽  
Yi-Ping Hsueh
Keyword(s):  
Rna Interference ◽  
Adhesion Molecules ◽  
Hippocampal Neurons ◽  
Time Course ◽  
Pdz Domain ◽  
Spine Density ◽  
Spine Formation ◽  
Protein 4.1 ◽  
Maguk Protein ◽  
Maguk Proteins

Membrane-associated guanylate kinase (MAGUK) proteins interact with several synaptogenesis-triggering adhesion molecules. However, direct evidence for the involvement of MAGUK proteins in synapse formation is lacking. In this study, we investigate the function of calcium/calmodulin-dependent serine protein kinase (CASK), a MAGUK protein, in dendritic spine formation by RNA interference. Knockdown of CASK in cultured hippocampal neurons reduces spine density and shrinks dendritic spines. Our analysis of the time course of RNA interference and CASK overexpression experiments further suggests that CASK stabilizes or maintains spine morphology. Experiments using only the CASK PDZ domain or a mutant lacking the protein 4.1–binding site indicate an involvement of CASK in linking transmembrane adhesion molecules and the actin cytoskeleton. We also find that CASK is SUMOylated. Conjugation of small ubiquitin-like modifier 1 (SUMO1) to CASK reduces the interaction between CASK and protein 4.1. Overexpression of a CASK–SUMO1 fusion construct, which mimicks CASK SUMOylation, impairs spine formation. Our study suggests that CASK contributes to spinogenesis and that this is controlled by SUMOylation.

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