MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes

Abstract

The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes.

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders

“…AKT phosphorylates GSK3β at serine 9, downregulating its activity ( Cross et al, 1994 ; Cross et al, 1995 ). The extracellular regulated kinase (ERK) pathway also has been implicated in neurological disorders and neural processes like extinction ( Radulovic and Tronson, 2010 ; Vithayathil et al, 2018 ; Albert-Gascó et al, 2020 ) and is a parallel signaling pathway to AKT that can have crosstalk ( York et al, 2000 ; Perkinton et al, 2002 ; Sutton and Chandler, 2002 ; Jones et al, 2003 ). ERK activity is regulated by phosphorylation of threonine 202/tyrosine 204 (ERK1) and threonine 185/tyrosine 187 (ERK2), which could be indirectly affected by AKT activity ( Ahn et al, 1990 ; Payne et al, 1991 ).…”

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…Furthermore, cAMP activates the exchange protein directly activated by cAMP (EPAC), which regulates kinases (e.g., ERK and Raf) and Rap GTP-binding protein, a small-GTPase similar to Ras. These factors have key roles in modulation of molecular signaling involved in various aspects of neuronal differentiation, like the establishment of neuronal polarity or axonal growth and cone movement [21][22][23][24] (Fig. 1).…”

Network pharmacology study on the mechanism of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel for anxiety disorders

“…The MAPK/ERK signaling pathway is a mechanism that mediates the transmission of extracellular signals to their intracellular targets. It affects the emotional function, social behavior, and spatial memory in humans and is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases (57). Acute local blockade of this MAPK signaling pathway in hypothalamic paraventricular nucleus (PVN) may cause a profound anxiogenic phenotype (58).…”