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.

Keywords: hippocampus; learning; long term depression; long term potentiation; memory; receptor; septum; synapse.

Figure 1

Schematic showing the main metabolic pathways in which MAPK/ERK signaling is involved. The ERK pathway can be activated by two main receptors, i.e., receptor tyrosine kinase (RTK) (i) and G-protein coupled receptor (GPCR) (ii). In addition, cytosolic mechanisms can also activate the pathway through protein kinase C (PKC) (iii) or calcium-calmodulin (CaM) (iv). The activation of the pathway can be directed by scaffolding proteins that hold together the components of the pathway. Once ERK is phosphorylated, cytoplasmic or nuclear changes may be induced, activating sets of genes responsible for neural differentiation, migration, the final fate, and plastic changes. Cytoplasmic p-ERK can promote processes such as apoptosis and neurogenesis.

Figure 2

Role of MAPK/ERK signaling in embryonic development. Signals mediated by ERK promote the migration of neural crest cells to their final fates, so that disturbance of this signaling pathway may result in alterations of craniofacial morphology (1), cardiac valves (2), the bronchopulmonary system (3), and the melanocyte distribution in the skin (4). Additionally, the encephalic patterning depends, in part, on encephalic signals transmitted from the isthmus (Is) and the anterior ridge (AR), which create a gradient of FGF8 that can trigger pERK signaling in different segments of the neural axis.

Figure 3

Scheme showing the development of the cerebral cortex and the role that MAPK/ERK signaling may have at different stages. Three main stages can be defined. The first stage is characterized by continuous divisions resulting in the expansion of the neural progenitor cell (NPC) pool. Starting at E11 until E17, the neurogenesis process is driven by ERK phosphorylation in the NPC, which suppresses gliogenesis. During neurogenesis, two kinds of divisions can be seen, i.e., asymmetric divisions (asd) and symmetric divisions (sd). Neuronal progenitors resulting from asd can derive intermediate progenitor cells (IPC) which divide in sd and cells resulting from these divisions migrate along the shafts of radial glia to the final fate. Inhibitory neurons in the cerebral cortex arise from tangential migration (TM) from the ganglionic eminences. Immature neurons produce signaling trophic factors mediated by MAPK/ERK signaling which induce gliogenesis, resulting in the generation of the different types of astrocytes. Throughout brain development, the cortex becomes layered from an initial period only composed of the ventricular zone (VZ) and the marginal zone. Then, newly born neurons are located in an intermediate layer that originates from the preplate (PP), which differentiates into the subventricular zone (SVZ), intermediate zone (IZ), and subplate (SP). Then, the area containing the neuronal bodies of neurons makes the cortical plate. Modified from [67].