Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders

Klocke, Benjamin; Krone, Kylie; Tornes, Jason; Moore, C. F.; Ott, Hayden; Pitychoutis, Pothitos M.

doi:10.3389/fnins.2023.1093099

Cited by 8 publications

(9 citation statements)

References 77 publications

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“…Moreover, the R451C NLGN3 cultures showed a slower calcium response after depolarization, in comparison to the WT cells. This is in agreement with the dysregulation of Ca 2+ concentration that is associated with several neurodevelopmental disorders, including ASDs 60 . Treatment of NSPCs cultures expressing endogenous R451C NLGN3, with DEX, improved mutant protein levels, both in proliferative and differentiated conditions, confirming the results obtained in the HEK‐293 cells.…”

Section: Discussionsupporting

confidence: 86%

“…This is in agreement with the dysregulation of Ca 2+ concentration that is associated with several neurodevelopmental disorders, including ASDs. 60 This could reflect a higher sensitivity of the NSPCs, where the endogenous mutant protein has a higher impact on the cellular homeostasis and the effect of DEX results in a stronger outcome. Unfortunately, it was not possible to evaluate whether DEX increased the localization of endogenous NLGN3 on the cell surface, therefore favoring the formation of synaptic contacts in differentiated cultures expressing R451C NLGN3, since the endogenous protein is not flag-tagged and there are no commercially available antibodies against NLGN3 to be used in immunostaining.…”

Section: Generation Of Neural Staminal Progenitor Cultures From Adult...mentioning

confidence: 99%

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Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation

Diamanti,

Trobiani,

Mautone

et al. 2024

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Neuroligins are synaptic cell adhesion proteins with a role in synaptic function, implicated in neurodevelopmental disorders. The autism spectrum disorder‐associated substitution Arg451Cys (R451C) in NLGN3 promotes a partial misfolding of the extracellular domain of the protein leading to retention in the endoplasmic reticulum (ER) and the induction of the unfolded protein response (UPR). The reduced trafficking of R451C NLGN3 to the cell surface leads to altered synaptic function and social behavior. A screening in HEK‐293 cells overexpressing NLGN3 of 2662 compounds (FDA‐approved small molecule drug library), led to the identification of several glucocorticoids such as alclometasone dipropionate, desonide, prednisolone sodium phosphate, and dexamethasone (DEX), with the ability to favor the exit of full‐length R451C NLGN3 from the ER. DEX improved the stability of R451C NLGN3 and trafficking to the cell surface, reduced the activation of the UPR, and increased the formation of artificial synapses between HEK‐293 and hippocampal primary neurons. The effect of DEX was validated on a novel model system represented by neural stem progenitor cells and differentiated neurons derived from the R451C NLGN3 knock‐in mouse, expressing the endogenous protein. This work shows a potential rescue strategy for an autism‐linked mutation affecting cell surface trafficking of a synaptic protein.

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Section: Discussionsupporting

confidence: 86%

Section: Generation Of Neural Staminal Progenitor Cultures From Adult...mentioning

confidence: 99%

Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation

Diamanti,

Trobiani,

Mautone

et al. 2024

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“…Previous studies have shown that the activation of ER stress is associated with the occurrence and development of ASD ( 19 , 21 ). The disruption of neuronal protein homeostasis ( 53 – 55 ), the dysregulation of calcium homeostasis ( 56 , 57 ), the induction of inflammatory cytokines, such as TNF-α ( 58 , 59 ), IL-33 ( 60 ), and IL-1β ( 61 ), and other pathways have all been proposed as contributing factors ( 59 ). Despite the previous role of ER stress in the pathophysiology of ASD has been highlighted, research on ER stress regulators in the ASD field remains in its infancy.…”

Section: Discussionmentioning

confidence: 99%

“…Previous research has shown the role of both adaptive and innate immune cells in the etiology of ASD. It was reported that a single injection of IL-6 into pregnant mice led to autism-relevant behaviors in the offspring, while blockade of IL-6 trans-signaling in the brain of mice could cause improved autism-like behavioral symptoms ( 56 , 57 ). Ahmed Nadeem and colleagues revealed that dysregulation in IL-6 receptors is associated with upregulated IL-17A-related signaling in children with autism, and the IL-6/IL-17A-related parameters are positively correlated with disease severity ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of endoplasmic reticulum stress regulators’ expression identifies distinct subtypes of autism spectrum disorder

Gao

Meng

2023

Front. Psychiatry

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Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in a variety of human diseases. However, their relevance to autism spectrum disorder (ASD) remains largely unknown. Herein, we aimed to investigate the expression patterns and potential roles of the ER stress regulators in ASD. The ASD expression profiles GSE111176 and GSE77103 were compiled from the Gene Expression Omnibus (GEO) database. ER stress score determined by the single sample gene set enrichment analysis (ssGSEA) was significantly higher in ASD patients. Differential analysis revealed that there were 37 ER stress regulators dysregulated in ASD. Based on their expression profile, the random forest and artificial neuron network techniques were applied to build a classifier that can effectively distinguish ASD from control samples among independent datasets. Weighted gene co-expression network analysis (WGCNA) screened out the turquoise module with 774 genes was closely related to the ER stress score. Through the overlapping results of the turquoise module and differential expression ER stress genes, hub regulators were gathered. The TF/miRNA-hub gene interaction networks were created. Furthermore, the consensus clustering algorithm was performed to cluster the ASD patients, and there were two ASD subclusters. Each subcluster has unique expression profiles, biological functions, and immunological characteristics. In ASD subcluster 1, the FAS pathway was more enriched, while subcluster 2 had a higher level of plasma cell infiltration as well as the BCR signaling pathway and interleukin receptor reaction reactivity. Finally, the Connectivity map (CMap) database was used to find prospective compounds that target various ASD subclusters. A total of 136 compounds were significantly enriched. In addition to some specific drugs which can effectively reverse the differential gene expression of each subcluster, we found that the PKC inhibitor BRD-K09991945 that targets Glycogen synthase kinase 3β (GSK3B) might have a therapeutic effect on both ASD subtypes that worth of the experimental validation. Our finding proved that ER stress plays a crucial role in the diversity and complexity of ASD, which may inform both mechanistic and therapeutic assessments of the disorder.

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“…Interestingly, SERCA-mediated Ca 2+ dyshomeostasis has been associated with various neuropathological conditions, including bipolar disorder, schizophrenia, Parkinson's disease, Alzheimer's disease, cerebral ischemia and alcoholism (Britzolaki et al, 2018(Britzolaki et al, , 2020. Further, disruption of SERCA and other key endoplasmic reticular Ca 2+ -regulators, such as the inositol triphosphate receptors and ryanodine receptors (RyR), has been implicated in the pathophysiology of autism spectrum disorders and the attention-deficit hyperactivity disorder (ADHD) (Klocke et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Chronic pharmacological activation of SERCA with CDN1163 affects spatial cognitive flexibility but not attention and impulsivity in mice

Klocke,

Moore,

Ott

et al. 2023

Behavioural Pharmacology

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Intracellular calcium (Ca2+) homeostasis is critical for many neural processes, including learning, memory and synaptic plasticity. The sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) is among the key regulators that preserve Ca2+ homeostasis in neurons. SERCAs comprise a set of ubiquitously expressed Ca2+ pumps that primarily function to sequester cytosolic Ca2+ into endoplasmic reticular stores. As SERCA has been implicated in the neurobiology of several neuropsychiatric and neurodegenerative diseases, pharmacological harnessing of its function is critical in understanding SERCA’s role in brain physiology and pathophysiology. In the current study, we employed the Morris water maze and 5-choice serial reaction time task (5-CSRTT) to investigate the effects of chronic pharmacological activation of SERCA, using the small allosteric SERCA activator CDN1163, on spatial learning and memory, and executive functioning in naive C57BL/6J mice. Our data show that chronic pharmacological SERCA activation with CDN1163 (20 mg/kg) selectively impairs spatial cognitive flexibility and reversal learning in the Morris water maze while leaving executive functions such as attention and impulsivity intact. Present findings contribute to the growing field of the role of SERCA function in the brain and behavior and expand current knowledge on the use of the small allosteric activator CDN1163 as an investigational tool to study the role of SERCA in regulating neurobehavioral processes and as a potential therapeutic candidate for debilitating brain disorders.

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Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders

Cited by 8 publications

References 77 publications

Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation

Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation

Integrated analysis of endoplasmic reticulum stress regulators’ expression identifies distinct subtypes of autism spectrum disorder

Chronic pharmacological activation of SERCA with CDN1163 affects spatial cognitive flexibility but not attention and impulsivity in mice

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