Serotonin 5‐HT7 receptors require cyclin‐dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome

Costa, Lara; Tempio, Alessandra; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia

doi:10.1111/ejn.15246

Cited by 9 publications

(5 citation statements)

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“…One such compound is LP-211 that reverses mGluR mediated long-term depression (LTD) in the hippocampus of wild type and Fmr1-KO mice and improves learning deficits as well as repetitive behavior in these mice (Costa et al, 2012(Costa et al, , 2015. Recent work from Costa et al (2021) further confirmed the LP-211 effect on mGluR-LTD and revealed that this compound requires cyclin-dependent kinase 5 to rescue abnormal plasticity in Fmr1-KO mice.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models

et al. 2023

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IntroductionAutism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology.MethodsThe GABAB receptor agonist R-Baclofen and the selective agonist for the 5HT7 serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR T+ Itpr3tf/J and B6.129P2-Fmr1tm1Cgr/J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests.ResultsBTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice’s ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice.ConclusionOur results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy.

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Section: Introductionmentioning

confidence: 99%

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models

et al. 2023

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“…Additionally, the activation of 5-HT receptors has emerged as a promising strategy for limiting neuroin ammation. By reducing astrocyte and microglial reactivity, 5-HT receptor activation protects the brain from in ammation-induced neurodegenerative changes [42,43]. The aforementioned studies primarily concentrated on the activation of hippocampal 5-HT receptors.…”

Section: Discussionmentioning

confidence: 99%

Tryptophan-rich diet and its effects on brain Tregs in alleviating neuroinflammation and cognitive impairment

Xue,

Guo,

Liu

et al. 2024

Preprint

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Background: Perioperative neurocognitive disorders (PND) present a common challenge for elderly people and contribute to increased postoperative dementia rates and mortality. Notably, neuroinflammation serves as a pivotal pathogenic mechanism for PND. Regulatory T cells (Tregs) exhibit potent anti-inflammatory properties and can modulate neurodegenerative diseases arising from central nervous system inflammatory responses. However, the role of Tregs in neuroinflammation-related PND remains unclear. It is highly plausible that brain Tregs expressing unique genes associated with the nervous system, including the Htr7 gene encoding the serotonin receptor 5-HT7, play a pivotal role. Methods: A model of neuroinflammation-mediated cognitive dysfunction was established via intracerebroventricular injection of lipopolysaccharide (LPS). The activation and infiltration of Tregs were measured using flow cytometry. Metagenomic sequencing of fecal samples was employed to investigate alterations in gut bacterial abundance following LPS administration. TMT-based quantitative proteomics analysis was employed to detect the proteomes of hippocampal tissue following LPS treatment. Primary Tregs were cocultured separately with primary CD8+ T cells and primary microglia for in vitro validation of the impact of 5-HT and Htr7 on Tregs. Prior to their transfer into recombination activating gene 1 (Rag1−/−) mice, Tregs were ex vivo transfected with lentivirus to knock down the expression of Htr7. Results: In this study, the tryptophan-rich diet was found to reverse LPS-induced cognitive impairment and reduce the levels of 5-HT in peripheral blood. Following intracerebroventricular microinjection of LPS, there was a decrease in the abundance of 5-HT-related gut microbiota. The tryptophan-rich diet led to increased levels of 5-HT in peripheral blood, which in turn promoted the proliferation and activation of brain Tregs. Additionally, proteomic alterations were observed in the hippocampus of the mice following LPS treatment. The tryptophan-rich diet was also shown to attenuate LPS-mediated neuroinflammation by activating brain Tregs. Furthermore, 5-HT and Htr7 were found to enhance the immunosuppressive effect of Tregs on CD8+ T cells and microglia. In Rag1-/- mice, brain Tregs were shown to alleviate LPS-induced neuroinflammation and cognitive impairment. Conclusions: Our research revealed the ability of brain Tregs to mitigate neuroinflammation and prevent neuronal damage by suppressing the infiltration of CD8+ T cells into the brain and excessive activation of microglia, thereby ameliorating LPS-induced cognitive impairment. These insights may offer novel therapeutic targets involving Tregs for PND.

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“…Downregulation of Cdk5 has been associated with attention deficit and hyperactivity disorder [ 110 ], epilepsy [ 111 ], and schizophrenia [ 112 ]. Cdk5 rescued hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a genetic form of intellectual disability associated with epilepsy, autism, and mood disorders, suggesting that activation of Cdk5 activity might be a pharmacological tool to treat Fragile X Syndrome [ 113 ]. However, no association between polymorphisms in Cdk5 with autism was found in a Chinese Han population [ 114 ].…”

Section: Cdk5 Knockdown and Zebrafish Motor Neurons: Relevance To Autismmentioning

confidence: 99%

Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism

Gu,

Kanungo

2024

IJMS

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The exact mechanisms of the development of autism, a multifactorial neurological disorder, are not clear. The pathophysiology of autism is complex, and investigations at the cellular and molecular levels are ongoing to provide clarity. Mutations in specific genes have been identified as risk factors for autism. The role of heavy metals in the pathogenesis of autism is subject to many studies and remains debatable. Although no exact neuronal phenotypes have been identified linked to autistic symptoms, overproduction and reduction of specific neurons have been implicated. A growing literature on generating genetic and non-genetic models of autism aims to help with understanding mechanistic studies that can explain the complexity of the disorder. Both genetic and non-genetic methods of zebrafish have been used to model autism. For several human autism risk genes, validated zebrafish mutant models have been generated. There is growing evidence indicating a potential link between autism and inorganic arsenic exposure. We have previously shown that inorganic arsenic induces supernumerary spinal motor neurons via Sonic hedgehog (Shh) signaling pathway, and Cdk5 knockdown causes an overproduction of cranial and spinal motor neurons in zebrafish. Here, in this review, we provide a perspective on what these findings of neurogenic phenotypes mean in terms of dysregulated pathways of motor neuron development and their applicability to understanding cellular and molecular underpinnings of autism.

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Serotonin 5‐HT7 receptors require cyclin‐dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 44 publications

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models

Tryptophan-rich diet and its effects on brain Tregs in alleviating neuroinflammation and cognitive impairment

Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism

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