scholarly journals Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

2019 ◽  
Author(s):  
Mathieu Letellier ◽  
Matthieu Lagardère ◽  
Béatrice Tessier ◽  
Harald Janovjak ◽  
Olivier Thoumine
Keyword(s):  
Tyrosine Phosphorylation ◽  
Ampa Receptors ◽  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Tyrosine Kinase Receptor ◽  
Spine Density ◽  
Light Stimulation ◽  
Knock Out ◽  
Synaptic Differentiation ◽  
The Impact

AbstractNeuroligins (Nlgs) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlg expression. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlg1 in CA1 hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 h selectively increased dendritic spine density and AMPA receptor-mediated EPSCs in wild-type neurons, but not in Nlg1 knock-out neurons or when endogenous Nlg1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP. Combined with computer simulations, our data support a model by which Nlg1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy thus highlights the impact of Nlg1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.Impact StatementOrthogonal to the traditional paradigms used to manipulate neuroligin expression level, the optogenetic trigger of tyrosine phosphorylation supports a strong role of endogenous neuroligin-1 in excitatory synaptic differentiation and potentiation.

scholarly journals Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mathieu Letellier ◽  
Matthieu Lagardère ◽  
Béatrice Tessier ◽  
Harald Janovjak ◽  
Olivier Thoumine
Keyword(s):  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Tyrosine Kinase Receptor ◽  
Dependent Manner ◽  
Spine Density ◽  
Light Stimulation ◽  
Knock Out ◽  
Synaptic Differentiation ◽  
The Impact

Neuroligins (Nlgns) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlgn expression level. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlgn1 in CA1 mouse hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 hr selectively increased dendritic spine density and AMPA-receptor-mediated EPSCs in wild-type neurons, but not in Nlgn1 knock-out neurons or when endogenous Nlgn1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP in a Nlgn1-dependent manner. Combined with computer simulations, our data support a model by which Nlgn1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy highlights the impact of Nlgn1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.

scholarly journals Preventing adolescent synaptic pruning in mouse prelimbic cortex via local knockdown of α4βδ GABAA receptors increases anxiety response in adulthood

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthew R. Evrard ◽  
Michael Li ◽  
Hui Shen ◽  
Sheryl S. Smith
Keyword(s):  
Gabaa Receptors ◽  
Adolescent Females ◽  
Prelimbic Cortex ◽  
Spine Density ◽  
Knock Out ◽  
Plus Maze ◽  
Anxiety Response ◽  
Global And Local ◽  
The Impact ◽  
Synaptic Pruning

AbstractAnxiety is increasingly reported, especially in adolescent females. The etiology is largely unknown, which limits effective treatment. Layer 5 prelimbic cortex (L5PL) increases anxiety responses but undergoes adolescent synaptic pruning, raising the question of the impact of pruning on anxiety. Here we show that preventing L5PL pruning increases anxiety in response to an aversive event in adolescent and adult female mice. Spine density of Golgi-stained neurons decreased ~ 63% from puberty (~ PND35, vaginal opening) to post-puberty (PND56, P < 0.0001). Expression of α4βδ GABAA receptors (GABARs) transiently increased tenfold in L5PL at puberty (P < 0.00001), but decreased post-pubertally. Both global and local knockdown of these receptors during puberty prevented pruning, increasing spine density post-pubertally (P < 0.0001), an effect reversed by blocking NMDA receptors (NMDARs). Pubertal expression of the NMDAR-dependent spine protein kalirin7 decreased (50%, P < 0.0001), an effect prevented by α4 knock-out, suggesting that α4βδ-induced reductions in kalirin7 underlie pruning. Increased spine density due to local α4 knockdown at puberty decreased open arm time on the elevated plus maze post-pubertally (62%, P < 0.0001) in response to an aversive stimulus, suggesting that increases in L5PL synapses increase anxiety responses. These findings suggest that prelimbic synaptic pruning is necessary to limit anxiety in adulthood and may suggest novel therapies.

Exogenous Neonatal Erythropoietin Mitigates Brain Damage After a Combination of Prenatal Hypoxic-Ischemia and Lipopolysaccharide Inflammation in Rats

2008 ◽  
Vol 1 (4) ◽  
pp. A353
Author(s):  
Shenandoah Robinson ◽  
Qing Li
Keyword(s):  
Brain Damage ◽  
Intracellular Signaling ◽  
System Development ◽  
Intrauterine Infection ◽  
Artery Occlusion ◽  
Nervous System Development ◽  
Human Infants ◽  
Hypoxic Ischemia ◽  
Show Evidence ◽  
The Impact

Introduction Many infants born very preterm who suffer brain damage most likely experienced a combined insult from intrauterine infection and placental insufficiency. Damage is thought to be synergistic rather than additive but the mechanisms of combined injury remain elusive. A combination of lipopolysaccharide-induced inflammation and hypoxia-ischemia has been used in rats to model the dual insult that occurs in human infants prenatally. Erythropoietin, a pleiotrophic cytokine that is essential for central nervous system development, ameliorates brain injury after isolated hypoxic-ischemic or inflammatory insults through different intracellular signaling pathways. We hypothesized that exogenous neonatal EPO administration would lessen the damage of a combined prenatal insult in rats. Methods On embryonic Day 18 fetal rats experienced 60 minutes of transient uterine artery occlusion with or without intracervical LPS administration with sham controls receiving surgery but no occlusion and saline for LPS. Survival was recorded and histological biochemical and functional assays were performed. Means were compared with ANOVA with Tukey HSD post hoc analysis. Results After a combined insult of HI and 0.15-mg/kg LPS on E18 the survival of pups by postnatal Day 1 (P1) decreased from 77% with HI alone to 22% for LPS plus HI. When exogenous systemic EPO was administered P1–P3 survival to P9 improved markedly from 40% (2 of 5) for saline-treated insult pups to 100% (6 of 6) for EPO-treated. Initial histological analyses show EPO decreases the number of brain activated caspase 3 and activated microglia by P9. Additional analyses will be presented. Conclusion As at least 60% of placentas from infants born pre-term show evidence of chorioamnionitis, assessment of the impact of exogenous EPO on a model of a combination injury is essential prior to proceeding with a clinical trial. Initial results indicate neonatal exogenous EPO mitigates damage from the combined insult.

scholarly journals Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

2021 ◽  
Vol 22 (8) ◽  
pp. 4269
Author(s):  
Simona Gribaudo ◽  
Daniele Saraulli ◽  
Giulia Nato ◽  
Sara Bonzano ◽  
Giovanna Gambarotta ◽  
...  
Keyword(s):  
Associative Memory ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Large Population ◽  
Adult Life ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Knock Out ◽  
Memory Impairments ◽  
Dependent Learning

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

scholarly journals Developmental up-regulation of NMDA receptors in the prefrontal cortex and hippocampus of mGlu5 receptor knock-out mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Tiziana Imbriglio ◽  
Remy Verhaeghe ◽  
Nico Antenucci ◽  
Stefania Maccari ◽  
Giuseppe Battaglia ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Adult Life ◽  
Developmental Time ◽  
Postnatal Life ◽  
Developmental Studies ◽  
Knock Out ◽  
Nmda Receptor Subunits ◽  
The Impact

AbstractmGlu5 metabotropic glutamate receptors are highly expressed and functional in the early postnatal life, and are known to positively modulate NMDA receptor function. Here, we examined the expression of NMDA receptor subunits and interneuron-related genes in the prefrontal cortex and hippocampus of mGlu5−/− mice and wild-type littermates at three developmental time points (PND9, − 21, and − 75). We were surprised to find that expression of all NMDA receptor subunits was greatly enhanced in mGlu5−/− mice at PND21. In contrast, at PND9, expression of the GluN2B subunit was enhanced, whereas expression of GluN2A and GluN2D subunits was reduced in both regions. These modifications were transient and disappeared in the adult life (PND75). Changes in the transcripts of interneuron-related genes (encoding parvalbumin, somatostatin, vasoactive intestinal peptide, reelin, and the two isoforms of glutamate decarboxylase) were also observed in mGlu5−/− mice across postnatal development. For example, the transcript encoding parvalbumin was up-regulated in the prefrontal cortex of mGlu5−/− mice at PND9 and PND21, whereas it was significantly reduced at PND75. These findings suggest that in mGlu5−/− mice a transient overexpression of NMDA receptor subunits may compensate for the lack of the NMDA receptor partner, mGlu5. Interestingly, in mGlu5−/− mice the behavioral response to the NMDA channel blocker, MK-801, was significantly increased at PND21, and largely reduced at PND75. The impact of adaptive changes in the expression of NMDA receptor subunits should be taken into account when mGlu5−/− mice are used for developmental studies.

scholarly journals Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

2021 ◽  
Vol 22 (11) ◽  
pp. 6047
Author(s):  
Mattias F. Lindberg ◽  
Laurent Meijer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Neuronal Development ◽  
Viral Infections ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Cell Cycle Control ◽  
Megakaryoblastic Leukemia ◽  
Dual Specificity

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

scholarly journals Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons

2015 ◽  
Vol 112 (19) ◽  
pp. 6176-6181 ◽  
Author(s):  
Olga Varea ◽  
Maria Dolores Martin-de-Saavedra ◽  
Katherine J. Kopeikina ◽  
Britta Schürmann ◽  
Hunter J. Fleming ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Knockout Mice ◽  
Copy Number Variations ◽  
Spine Density ◽  
Structured Illumination ◽  
Single Nucleotide Variants ◽  
Glutamatergic Synapses ◽  
Superresolution Microscopy ◽  
Synaptic Markers ◽  
Cellular Phenotypes

Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.

Blockage of IL-17 Ameliorates Aβ-Induced Neurotoxicity and Cognitive Decline

2021 ◽  
Author(s):  
Yulan Liu ◽  
Yang Meng ◽  
Chenliang Zhou ◽  
Wenfang Xia ◽  
Lu Wang ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Lateral Ventricle ◽  
Hippocampal Neurons ◽  
Cognitive Impairments ◽  
Critical Role ◽  
Synaptic Dysfunction ◽  
Neural Damage ◽  
Primary Hippocampal Neurons ◽  
The Impact ◽  
Aβ Production

Abstract BackgroundNeuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease (AD), particularly in amyloid-β (Aβ) production. But the impact of the cytokine, interleukin-17A (IL-17) on the course of AD has not been well defined. The goal was to determine the effect of IL-17 on neural damage and whether IL-17 inhibitor (Y-320) could ameliorate Aβ-induced neurotoxicity and cognitive decline.MethodsThe expression level of IL-17 was analyzed in APP/PS1 mice. Then IL-17 was injected into the lateral ventricle of C57BL WT mice and roles on synaptic dysfunction and cognitive impairments were examined. Aβ42 was injected into the lateral ventricle of to mimic Aβ42 model mice. The effects of IL-17 inhibitor by oral gavage on Aβ42-induced neurotoxicity and cognitive decline were examined. ResultsWe found that IL-17 was increased in the hippocampus of APP/PS1 transgenic mouse, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Furthermore, we reported that IL-17 was administrated in primary hippocampal neurons, leading to neural damage and synaptic dysfunction. At the same time, IL-17 caused synaptic dysfunction and cognitive impairments accompanying with increased of Aβ levels in mice. In addition, we found that Y-320 could rescue Aβ42–induced neural damage in primary hippocampal neurons, and ameliorate neuronal damage and cognitive impairments in Aβ42 model mice. Interestingly, we observed that IL-17 upregulated the production of soluble amyloid precursor protein β (sAPPβ) and phosphorylation of APP at T668 (pT668), moreover, Y-320 inhibited the Aβ production by down-regulation the sAPPβ and pT668. Conclusions Blockage of IL-17 might ameliorate Aβ-induced neurotoxicity and cognitive decline. These results strongly demonstrate a potential therapeutic role for IL-17 inhibitor in AD.

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