Involvement of p38 MAPK in Synaptic Function and Dysfunction

Falcicchia, Chiara; Tozzi, Francesca; Arancio, Ottavio; Watterson, Daniel; Origlia, Nicola

doi:10.3390/ijms21165624

Cited by 127 publications

(88 citation statements)

References 87 publications

(142 reference statements)

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“…It is noteworthy that P38 MAPK module activation plays a pivotal role in inflammatory responses and cytokine release [ 69 ] and that increased inflammation in the central nervous system is a hallmark of psychiatric diseases in humans [ 18 ]. Dopamine is also an important regulator of cytokine secretion, regulating immune response [ 70 ] and neuropsychiatric disorders where aberrant DA neurotransmission is involved, such as PTSD and schizophrenia, displaying increased CNS inflammation [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

et al. 2021

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Monoamine dysfunctions in the prefrontal cortex (PFC) can contribute to diverse neuropsychiatric disorders, including ADHD, bipolar disorder, PTSD and depression. Disrupted dopamine (DA) homeostasis, and more specifically dopamine transporter (DAT) alterations, have been reported in a variety of psychiatric and neurodegenerative disorders. Recent studies using female adult rats heterozygous (DAT+/−) and homozygous (DAT−/−) for DAT gene, showed the utility of those rats in the study of PTSD and ADHD. Currently, a gap in the knowledge of these disorders affecting adolescent females still represents a major limit for the development of appropriate treatments. The present work focuses on the characterization of the PFC function under conditions of heterozygous and homozygous ablation of DAT during early adolescence based on the known implication of DAT and PFC DA in psychopathology during adolescence. We report herein that genetic ablation of DAT in the early adolescent PFC of female rats leads to changes in neuronal and glial cell homeostasis. In brief, we observed a concurrent hyperactive phenotype, accompanied by PFC alterations in glutamatergic neurotransmission, signs of neurodegeneration and glial activation in DAT-ablated rats. The present study provides further understanding of underlying neuroinflammatory pathological processes that occur in DAT-ablated female rats, what can provide novel investigational approaches in human diseases.

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Section: Discussionmentioning

confidence: 99%

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

et al. 2021

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“…Several studies have described that p38 MAPKs promotes neuronal death induced by a variety of noxious stimuli, including inflammatory cytokines and neurotoxins [ 297 , 298 ], oxidative stress [ 299 , 300 ], hypoxic insult [ 301 ], and excitotoxicity [ 302 ]. For example, following neuronal damage or injury to the brain or spinal cord, p38 MAPK (and primarily p38α) promotes chronic inflammation through release of cytokines, including IL-1b and TNFa, from astrocytes and microglia, which while designed to be helpful has an inhibitory effect on recovery from injury [ 181 , 287 , 303 ]. IL-1b and TNFa released by microglia through the action of p38 MAPK also inhibit LTP and therefore synaptic plasticity [ 304 ].…”

Section: The Enzymesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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“…Their downregulation resulted in decreased synaptic function, mood changes, and cognitive impairments such as depression and anxiety [ 40 – 42 ]. Another possible mechanism revealed the role of p38 MAPK in neuronal plasticity and synaptic regulation and suggested that the activation of the p38 MAPK signaling pathway damages synaptic function, for which we have also validated the p38 MAPK pathway [ 43 ]. Interestingly, recent studies have uncovered that the MAPK signaling pathway is involved in the occurrence of depression, and blocking the MAPK signaling pathway can alleviate depression.…”

Section: Discussionmentioning

confidence: 81%

Low‐Dose Copper Exposure Exacerbates Depression‐Like Behavior in ApoE4 Transgenic Mice

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation.

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Involvement of p38 MAPK in Synaptic Function and Dysfunction

Cited by 127 publications

References 87 publications

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

Low‐Dose Copper Exposure Exacerbates Depression‐Like Behavior in ApoE4 Transgenic Mice

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