BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABA<sub>A</sub> receptor trafficking

Tomoda, Toshifumi; Sumitomo, Akiko; Shukla, Rammohan; Hirota-Tsuyada, Yuki; Miyachi, Hitoshi; Oh, Hyuncheol; French, Leon; Sibille, Etienne

doi:10.1101/334466

Cited by 2 publications

(2 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that the BDNF-TrkB system regulates GABAergic neurotransmission by different mechanisms, modulating expression (Bulleit et al, 2000;Roberts et al, 2006), phosphorylation (Vithlani et al, 2013) and trafficking (Brünig et al, 2001;Tomoda et al, 2022) of GABA A receptors, GABA release (Bardoni et al, 2007;Vaz et al, 2015), GABA transporter GAT-1 (Vaz et al, 2011), the function of the potassium-chloride co-transporter 2 (KCC2), which fine-tune intracellular chloride and the intensity of GABA A receptor currents (Dai et al, 2014) and the expression of the GABA-synthesizing enzyme GAD67 (Arenas et al, 1996).…”

Section: Tnfα-tnfr1-s1pr2-ccl2-bdnf-trkb Pathwaymentioning

confidence: 99%

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Llansola,

Arenas,

Sancho-Alonso

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Enhanced GABAergic neurotransmission contributes to impairment of motor coordination and gait and of cognitive function in different pathologies, including hyperammonemia and hepatic encephalopathy. Neuroinflammation is a main contributor to enhancement of GABAergic neurotransmission through increased activation of different pathways. For example, enhanced activation of the TNFα–TNFR1-NF-κB-glutaminase-GAT3 pathway and the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway in cerebellum of hyperammonemic rats enhances GABAergic neurotransmission. This is mediated by mechanisms affecting GABA synthesizing enzymes GAD67 and GAD65, total and extracellular GABA levels, membrane expression of GABAA receptor subunits, of GABA transporters GAT1 and GAT three and of chloride co-transporters. Reducing neuroinflammation reverses these changes, normalizes GABAergic neurotransmission and restores motor coordination. There is an interplay between GABAergic neurotransmission and neuroinflammation, which modulate each other and altogether modulate motor coordination and cognitive function. In this way, neuroinflammation may be also reduced by reducing GABAergic neurotransmission, which may also improve cognitive and motor function in pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission such as hyperammonemia, hepatic encephalopathy or Parkinson’s disease. This provides therapeutic targets that may be modulated to improve cognitive and motor function and other alterations such as fatigue in a wide range of pathologies. As a proof of concept it has been shown that antagonists of GABAA receptors such as bicuculline reduces neuroinflammation and improves cognitive and motor function impairment in rat models of hyperammonemia and hepatic encephalopathy. Antagonists of GABAA receptors are not ideal therapeutic tools because they can induce secondary effects. As a more effective treatment to reduce GABAergic neurotransmission new compounds modulating it by other mechanisms are being developed. Golexanolone reduces GABAergic neurotransmission by reducing the potentiation of GABAA receptor activation by neurosteroids such as allopregnanolone. Golexanolone reduces neuroinflammation and GABAergic neurotransmission in animal models of hyperammonemia, hepatic encephalopathy and cholestasis and this is associated with improvement of fatigue, cognitive impairment and motor incoordination. This type of compounds may be useful therapeutic tools to improve cognitive and motor function in different pathologies associated with neuroinflammation and increased GABAergic neurotransmission.

show abstract

Section: Tnfα-tnfr1-s1pr2-ccl2-bdnf-trkb Pathwaymentioning

confidence: 99%

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Llansola,

Arenas,

Sancho-Alonso

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…To visualize dendritic and spine morphology of major output neurons in culture, we prepared primary cortical neurons (61)…”

Section: Primary Cortical Neurons In Culture and Morphometric Analysismentioning

confidence: 99%

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Prevot

Sumitomo

Tomoda

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years.With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death.Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer's disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

show abstract

BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABA_A receptor trafficking

Cited by 2 publications

References 55 publications

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Contact Info

Product

Resources

About

BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABAA receptor trafficking

Cited by 2 publications

References 55 publications

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Contact Info

Product

Resources

About

BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABA_A receptor trafficking