scholarly journals Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lauren Tereshko ◽  
Ya Gao ◽  
Brian A Cary ◽  
Gina G Turrigiano ◽  
Piali Sengupta
Keyword(s):  
Primary Cilia ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Somatostatin Receptor ◽  
Cognitive Disorders ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Ciliary Signaling ◽  
Neocortical Pyramidal Neurons

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

scholarly journals Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

2020 ◽  
Author(s):  
Lauren Tereshko ◽  
Ya Gao ◽  
Brian A. Cary ◽  
Gina G. Turrigiano ◽  
Piali Sengupta
Keyword(s):  
Primary Cilia ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Somatostatin Receptor ◽  
Cognitive Disorders ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Ciliary Signaling ◽  
Neocortical Pyramidal Neurons

ABSTRACTPrimary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to pyramidal neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

scholarly journals Recruitment of β-arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

2015 ◽  
pp. MCB.00765-15 ◽  
Author(s):  
Jill A. Green ◽  
Cullen L. Schmid ◽  
Elizabeth Bley ◽  
Paula C. Monsma ◽  
Anthony Brown ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Somatostatin Receptor ◽  
Mammalian Brain ◽  
Receptor Subtype ◽  
Neuronal Cilia ◽  
Ciliary Function ◽  
Signaling Organelles ◽  
Subtype 3 ◽  
Ciliary Signaling ◽  
Ciliary Localization

Primary cilia are essential sensory and signaling organelles present on nearly every mammalian cell type. Defects in primary cilia underlie a class of human diseases collectively termed ciliopathies. Primary cilia are restricted subcellular compartments and specialized mechanisms coordinate localization of proteins to cilia. Moreover, trafficking of proteins into and out of cilia is required for proper ciliary function and this process is disrupted in ciliopathies. The somatostatin receptor subtype 3 (Sstr3) is selectively targeted to primary cilia on neurons in the mammalian brain and is implicated in learning and memory. Here, we show that Sstr3 localization to cilia is dynamic and decreases in response to somatostatin treatment. We further show that somatostatin treatment stimulates β-arrestin recruitment into Sstr3-positive cilia and this recruitment can be blocked by mutations in Sstr3 that impact agonist binding or phosphorylation. Importantly, somatostatin treatment fails to decrease Sstr3 ciliary localization in neurons lacking β-arrestin 2. Together, our results implicate β-arrestin in the modulation of Sstr3 ciliary localization and further suggest a role for β-arrestin in the mediation of Sstr3 ciliary signaling.

scholarly journals Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Samuel Teo ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Model Systems ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Wnt Ligands

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

scholarly journals Distinct in vivo dynamics of excitatory synapses onto cortical pyramidal neurons and parvalbumin-positive interneurons

Cell Reports ◽  
2021 ◽  
Vol 37 (6) ◽  
pp. 109972
Author(s):  
Joshua B. Melander ◽  
Aran Nayebi ◽  
Bart C. Jongbloets ◽  
Dale A. Fortin ◽  
Maozhen Qin ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Excitatory Synapses ◽  
Cortical Pyramidal Neurons

scholarly journals N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility

2019 ◽  
Vol 116 (42) ◽  
pp. 21207-21212 ◽  
Author(s):  
Hong Liu ◽  
Hao Wang ◽  
Matthew Peterson ◽  
Wen Zhang ◽  
Guoqiang Hou ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Developmental Change ◽  
Brain Regions ◽  
Excitatory Synapses ◽  
Seizure Susceptibility ◽  
Adult Mice ◽  
Splicing Variants ◽  
Functional Analyses ◽  
Developmental Remodeling

The majority of NMDA receptors (NMDARs) in the brain are composed of 2 GluN1 and 2 GluN2 subunits. The inclusion or exclusion of 1 N-terminal and 2 C-terminal domains of GluN1 results in 8 splicing variants that exhibit distinct temporal and spatial patterns of expression and functional properties. However, previous functional analyses of Grin1 variants have been done using heterologous expression and the in vivo function of Grin1 splicing is unknown. Here we show that N-terminal splicing of GluN1 has important functions in the maturation of excitatory synapses. The inclusion of exon 5 of Grin1 is up-regulated in several brain regions such as the thalamus and neocortex. We find that deletion of Grin1 exon 5 disrupts the developmental remodeling of NMDARs in thalamic neurons and the effect is distinct from that of Grin2a (GluN2A) deletion. Deletion of Grin2a or exon 5 of Grin1 alone partially attenuates the shortening of NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) during early life, whereas deletion of both Grin2a and exon 5 of Grin1 completely abolishes the developmental change in NMDAR-EPSC decay time. Deletion of exon 5 of Grin1 leads to an overproduction of excitatory synapses in layer 5 pyramidal neurons in the cortex and increases seizure susceptibility in adult mice. Our findings demonstrate that N-terminal splicing of GluN1 has important functions in synaptic maturation and neuronal network excitability.

scholarly journals Dendritic spine geometry can localize GTPase signaling in neurons

2015 ◽  
Vol 26 (22) ◽  
pp. 4171-4181 ◽  
Author(s):  
Samuel A. Ramirez ◽  
Sridhar Raghavachari ◽  
Daniel J. Lew
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Primary Cilia ◽  
Reaction Diffusion ◽  
Reaction Diffusion Equations ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Sustained Activation

Dendritic spines are the postsynaptic terminals of most excitatory synapses in the mammalian brain. Learning and memory are associated with long-lasting structural remodeling of dendritic spines through an actin-mediated process regulated by the Rho-family GTPases RhoA, Rac, and Cdc42. These GTPases undergo sustained activation after synaptic stimulation, but whereas Rho activity can spread from the stimulated spine, Cdc42 activity remains localized to the stimulated spine. Because Cdc42 itself diffuses rapidly in and out of the spine, the basis for the retention of Cdc42 activity in the stimulated spine long after synaptic stimulation has ceased is unclear. Here we model the spread of Cdc42 activation at dendritic spines by means of reaction-diffusion equations solved on spine-like geometries. Excitable behavior arising from positive feedback in Cdc42 activation leads to spreading waves of Cdc42 activity. However, because of the very narrow neck of the dendritic spine, wave propagation is halted through a phenomenon we term geometrical wave-pinning. We show that this can account for the localization of Cdc42 activity in the stimulated spine, and, of interest, retention is enhanced by high diffusivity of Cdc42. Our findings are broadly applicable to other instances of signaling in extreme geometries, including filopodia and primary cilia.

scholarly journals Propofol impairs specification of retinal cell types in zebrafish by inhibiting Zisp-mediated Noggin-1 palmitoylation and trafficking

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoqing Fan ◽  
Haoran Yang ◽  
Lizhu Hu ◽  
Delong Wang ◽  
Ruiting Wang ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Cell Formation ◽  
Cognitive Disorders ◽  
Cell Types ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Retinal Cell ◽  
Soluble Form ◽  
In Vivo Experiments

Abstract Background Propofol can have adverse effects on developing neurons, leading to cognitive disorders, but the mechanism of such an effect remains elusive. Here, we aimed to investigate the effect of propofol on neuronal development in zebrafish and to identify the molecular mechanism(s) involved in this pathway. Methods The effect of propofol on neuronal development was demonstrated by a series of in vitro and in vivo experiments. mRNA injections, whole-mount in situ hybridization and immunohistochemistry, quantitative real-time polymerase chain reaction, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, 5-ethynyl-2′-deoxyuridine labeling, co-immunoprecipitation, and acyl–biotin exchange labeling were used to identify the potential mechanisms of propofol-mediated zisp expression and determine its effect on the specification of retinal cell types. Results Propofol impaired the specification of retinal cell types, thereby inhibiting neuronal and glial cell formation in retinas, mainly through the inhibition of Zisp expression. Furthermore, Zisp promoted the stabilization and secretion of a soluble form of the membrane-associated protein Noggin-1, a specific palmitoylation substrate. Conclusions Propofol caused a severe phenotype during neuronal development in zebrafish. Our findings established a direct link between an anesthetic agent and protein palmitoylation in the regulation of neuronal development. This could be used to investigate the mechanisms via which the improper use of propofol might result in neuronal defects.

In vivo dendritic calcium dynamics in neocortical pyramidal neurons

Nature ◽  
1997 ◽  
Vol 385 (6612) ◽  
pp. 161-165 ◽  
Author(s):  
Karel Svoboda ◽  
Winfried Denk ◽  
David Kleinfeld ◽  
David W. Tank
Keyword(s):  
Pyramidal Neurons ◽  
Calcium Dynamics ◽  
Neocortical Pyramidal Neurons

Propofol Impairs Specification of Retinal Cell Types in Zebrafish by Inhibiting Zisp-mediated Noggin-1 Palmitoylation and Trafficking

2020 ◽  
Author(s):  
Xiaoqing Fan ◽  
Haoran Yang ◽  
Lizhu Hu ◽  
Delong Wang ◽  
Ruiting Wang ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Cell Formation ◽  
Cognitive Disorders ◽  
Cell Types ◽  
Retinal Cell ◽  
Soluble Form ◽  
In Vivo Experiments ◽  
Developing Neurons

Abstract Background: Propofol can have adverse effects on developing neurons, leading to cognitive disorders. However, the mechanism remains elusive. Here, we aimed to investigate the effect and molecular mechanism of propofol on neuronal development in zebrafish. Methods: The effect of propofol on neuronal development was demonstrated by a series of in vitro and in vivo experiments. mRNA injections, Whole-mount in situ hybridization and immunohistochemistry, quantitative real-time PCR, TUNEL, EdU, Co-Immunoprecipitation and acyl–biotin exchange (ABE) labeling method were carried out to demonstrate the potential mechanisms of propofol-mediated zisp expression and specification of retinal cell types.Results: Propofol impaired the specification of retinal cell types, thereby inhibiting neuronal and glial cell formation in retinas, mainly through inhibition of Zisp expression. Furthermore, Zisp promoted the secretion of a soluble form and the stabilization of a membrane-associated form of Noggin-1, a specific palmitoylation substrate.Conclusions: Propofol caused a severe phenotype during neuronal development in zebrafish. Our findings established a direct link between an anesthetic agent and protein palmitoylation in the regulation of neuronal development. This could be used to investigate the mechanisms via which the improper use of propofol might result in neuronal defects.

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