{"id":57764,"date":"2024-06-25T11:50:42","date_gmt":"2024-06-25T11:50:42","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=57764"},"modified":"2024-07-03T16:46:18","modified_gmt":"2024-07-03T16:46:18","slug":"the-impact-of-early-growth-response-1-egr1-on-hippocampal-synaptic-plasticity-and-cognitive-function-narrative-review","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no2\/the-impact-of-early-growth-response-1-egr1-on-hippocampal-synaptic-plasticity-and-cognitive-function-narrative-review\/","title":{"rendered":"The Impact of Early Growth Response 1 (Egr1) on Hippocampal Synaptic Plasticity and Cognitive Function: Narrative Review"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Early Growth Response 1 (EGR1) is a\ngene that plays a role in cognitive processes. Different members of the Egr\nfamily of transcriptional regulators have distinct functions in cognitive\nprocesses, with Egr1 being required specifically for long-term memory, while\nEgr3 is primarily essential for short-term memory1<\/sup>.  EGR\n1  in the\ncentral nervous system is a mediator of the interaction of genes with the environment and how environmental stimuli trigger rapid\nresponses and lasting neural adaptations\nto neuronal function and plasticity2,3<\/sup>. EGR1 is activated by several external stimuli, such as growth factors, and cytokinin stimuli4,5<\/sup>.\nWhen activated, the EGR1 protein binds to a specific\nDNA region called an early growth response\nelement (ERE) located in the promoter\nof a target gene6<\/sup>. <\/p>\n\n\n\n

After EGR1, mRNA levels are\ncharacterized by their rapid upregulation within minutes. It is not related to\nprotein synthesis, which is activated by general intracellular signaling\npathways such as the triphosphoinositide kinase (PI3K) pathway or the mitogen-activated\nkinase (MAPK) pathway and can be triggered by various stimuli\n2,6,7<\/sup>. Despite their extensive and overlapping nature, each EGR 1 differs in its activator, downstream regulatory pathway, target, and expression pattern1,2,6,8<\/sup>. Early\ngrowth response 1 (EGR1) underlies brain activity, including neurotransmission,\nsynaptic plasticity, and learning and memory processes. In this article, We\nemphasize the function of EGR1 in both physiological states of the CNS. Before\nanalyzing the genes, pathways, and biological processes that are targets of\nEGR1 in the CNS, we provide a summary of the variables that regulate its\nexpression.<\/p>\n\n\n\n

Method<\/strong><\/p>\n\n\n\n

Literature search using data\nbased Pubmed, Science direct and Scopus online. The data used is from year 1978\nuntil year 2022. Searched using English keywords such as EGR 1 and hippocampus.<\/p>\n\n\n\n

Result and Discussion<\/strong><\/strong><\/p>\n\n\n\n

 Nearly three decades ago EGR 1 was first\ndiscovered to be cloned to be regulated by nerve growth factor (NGF) in the\npresence of a protein synthesis inhibitor while screening the  cycloheximide9<\/sup> in mouse PC12 cells.<\/strong>  The\nprocess of cloning and characterization of this protein is carried out\nsimultaneously in different groups in different cell lines stimulated by growth\nfactors, which explains its alternative name: EGR110<\/sup>, NGFI-A9<\/sup>, Krox -2411<\/sup>, TIS85<\/sup>, and\nZif26812<\/sup>. The screening strategy identified EGR3, EGR4 and EGR2, which\ntogether with EGR1 form the EGR family6,8<\/sup>.<\/p>\n\n\n\n

All\nEGRs among species in the region contain three\ncysteine-2-histidine-two-zinc-finger (C2H2) DNA-binding domains and are\nhomologous, indicating similarities in the DNA sequences recognized by each EGR\nprotein and thus can overlap. In the purpose and function of EGR1, EGR2, and\nEGR3, but not EGR4, exhibit interaction domains with the transcriptional\nco-repressors NGFI-A-1\/2 (NAB1 and NAB2), in addition, exerting negative\ncontrol on transcriptional activity. Upregulation of EGR13<\/sup>, EGR1,\nEGR2 and EGR3 proteins may lead to suppression of their transcriptional role,\npartly supported by in vivo experimental evidence 14,15<\/sup>.<\/p>\n\n\n\n

EGR1 is common in\nhumans and many other animal species.\nThis gene is located on chromosome 5 at the 5q31 locus. The EGR1 protein acts\nas a transcription factor, a molecule that regulates gene expression by binding\nto DNA and regulating the activity of\ntarget genes. Thus, it is imperative to align the amino acid sequences of all human, rat, and mouse EGR protein due to\ndifferent regulation, transcriptional regulation, reactivity, neural function\nbetween EGR protein and protein interactions8<\/sup>.  <\/p>\n\n\n\n

EGR1\nexpression is undetectable in the nervous system of both embryos16,17<\/sup>,\nduring postnatal development and its expression continues to slowly increase\nuntil adulthood, namely on postnatal day 17 in the mouse brain18<\/sup>. The\ngradual increase in EGR1 expression, closely corresponds to the period of\nmaximal N-methyl-D-aspartate (NMDA) response and coincides with the time of\nsynaptic formation in the CA1 and hippocampal cortical regions, increasing\nlong-term inducibility (LTP)18<\/sup>. Establishing a link between EGR1 expression and synaptic plasticity. In adulthood, EGR1 is widely expressed throughout the\nbrain, which tends to control cognition,\nincluding the hippocampus6,19,20<\/sup>. Thus, EGR1 plays a crucial role\nin learning and memory, as its activity increases in brain regions involved in cognitive function.<\/p>\n\n\n\n

EGR<\/strong> <\/strong>1 And Synaptic Plasticity<\/strong> <\/strong><\/strong><\/p>\n\n\n\n

 The dentate hippocampus is an integral\npart of the brain involved in memory formation and storage. EGR 1 is critical\nin regulating tooth learning15<\/sup>. The signaling process of\nEGR1 expression and signal transmission\nto neuronal synapses involves several\ncomplex steps. The EGR1 signaling pathway is triggered by an external stimulus, such as new learning or interesting stimuli. This stimulus activates neurons in the brain and triggers a series\nof biochemical and electrochemical changes in the cells4<\/sup>. An external stimulus causes a change in\nthe membrane potential of neurons, which\ntriggers the release of neurotransmitters at presynaptic synapses. These neurotransmitters bind to receptors\non the postsynaptic cell membrane and initiate signaling through signaling pathways. When a neurotransmitter binds to\na receptor, it activates the receptor. Receptors are composed of protein subunits and have a central function in transmitting signals to the cell. Activation of the receptor triggers a series of biochemical and molecular\nchanges in the cell. EGR1 expression\nis often accompanied by  MAPK signaling pathway and the\nprotein kinase A (PKA) pathway4<\/sup>.<\/p>\n\n\n\n

 Activation of the receptor triggers the activation\nof MAP kinase, which is responsible for the phosphorylation and activation of\nthe Ras protein. Ras then activates a series of protein kinases, including MEK\n(MAPK\/ERK kinase) and ERK (extracellular signal-regulated kinase). ERK then translocates to the cell nucleus and phosphorylates a\ntranscription factor such as Elk-1, which interacts with the early growth\nresponse element (ERE) in the EGR1 gene promoter to initiate gene expression4<\/sup>. Activation of the receptor can also trigger activation of the PKA pathway. PKA\nphosphorylates transcription factors such as CREB (cAMP response element\nbinding protein). Phosphorylation of CREB triggers interactions with transcriptional co-activators, including EGR1. This CREB-EGR1 complex binds to the\nERE region of the EGR1 gene promoter to\namplify the gene21<\/sup>.  <\/p>\n\n\n\n

After activation of\nsignaling pathways, transcription factors such as Elk-1, CREB, and EGR1 move\nto the cell nucleus. In the cell nucleus, these factors interact with the ERE\nregion of the EGR1 gene promoter. This\ninteraction triggers the transcription\nand synthesis of EGR1 mRNA. The newly synthesized mRNA is then translated into\nthe EGR1 protein in the cytoplasm of the cell. The EGR1 protein is then transported back to the cell nucleus\nwhere it functions as a transcription factor. After returning to the cell nucleus, the EGR1 protein binds\nto the ERE region of the target gene promoter. It modulates the transcriptional activity\nof target genes involved in memory formation and storage15<\/sup>. <\/p>\n\n\n\n

 EGR1 expression and regulation of its target\ngenes influence synapse modification. This can include structural changes, such as the increase or elimination\nof synaptic spikes, as well as changes in\nthe release of neurotransmitters and the sensitivity of the receptor15<\/sup>. Through these steps, the EGR1 signaling\npathway influences gene expression and synaptic\nmodifications that promote learning and\nmemory processes in neurons. However, it is important to remember that these explanations are descriptive and the complexity of signaling mechanisms can vary\ndepending on the context and type of stimulus.<\/p>\n\n\n\n

EGR 1, Synaptic\nPlasticity and Exercise   <\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Exercise triggers the release of neural activity factor, intracellular signaling pathways, AMPK, cAMP, MAPK, or AKT are activated<\/strong>4<\/sup><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

 Physical exercise can influence\ngene expression through complex signaling pathways22<\/sup>. Intense\nand regular physical exercise can provide the body with external stimulation. This stimulation can occur during\naerobic activity or other stressful\nactivities that affect the nervous system\n23<\/sup>.\nPhysical exercise activates the nervous\nsystem, especially the autonomic and central nervous systems24<\/sup>. This activation releases neurotransmitters\nand peptides that play a role in nerve signal transmission25<\/sup>.<\/p>\n\n\n\n

 During physical exercise, muscle activity\nincreases, which can activate the AMPK.  Biochemical changes in AMPK cells can be\ntriggered by phosphorylation of transcription factors such as CREB. Physical\nexercise can also trigger MAPK pathways, such as the ERK (extracellular\nsignal-regulated kinase) pathway. Activation of the MAPK pathway can trigger\nthe phosphorylation of transcription\nfactors involved in EGR1 expression, such as Elk-1. Activation of transcription factors such as CREB and\nElk-1 can interact with the early growth\nresponse elements (ERE) of the EGR1 gene promoter. This initiates the process of transcription and synthesis\nof EGR1 mRNA.  The newly synthesized\nEGR1 mRNA is then translated into EGR1 protein in the cytoplasm, then functions\nas a transcription factor after the EGR1 protein is transported to the cell\nnucleus. When the EGR1 protein returns to the cell nucleus, it binds to the ERE\nregion of the target gene promoter. This gene functions to regulate target\ngenes involved in regulated physiological responses and adaptation to physical\nconditions exercise4<\/sup> (Figure 1).<\/p>\n\n\n\n

 Physical activity can trigger the expression\nof the EGR 1 gene to increase blood flow and neurotrophic factors, such as\nbrain-derived neurotrophic factor (BDNF) which plays a role in nerve growth and\ndevelopment26<\/sup>. This neurotrophic factor can stimulate EGR1\nexpression in the hippocampus, which regulates synaptic plasticity, an important mechanism for learning and memory15<\/sup>. Exercise can also\nhave neuroprotective effects on the brain, including the hippocampus. Increased\nexpression of EGR1 may play a role in protecting and restoring brain function\ndisrupted by oxidative stress or cell damage27,28<\/sup>. <\/p>\n\n\n\n

 Exercise can increase EGR1 gene expression\nin the brain as a whole. This may occur because physical activity increases\nblood flow and neurotrophic factors, such as  BDNF, which can stimulate EGR1 expression in\nneurons23,26<\/sup>. Regular exercise has been shown to protect\nnerves and improve nerve health. Several studies\nin which EGR1 expression can\npromote neuroprotection and recovery of impaired neuronal function23<\/sup>. Exercise can also increase neural\nplasticity, namely the ability of the nervous system to adapt and make new\nconnections between neurons29<\/sup>. Although direct studies have not\nexamined the effect of exercise on EGR1 expression in plastic neurons, higher\nEGR1 expression may play a role in the regulation of plastic neurons and the formation of new synaptic connections30,31<\/sup>.<\/p>\n\n\n\n

EGR1\nexpression, and neurological health greatly requires further research to\nunderstand the precise relationship between exercise. Variables such as exercise type, duration, intensity, and\nindividual characteristics can also affect\ncognitive function. A recent study and a more comprehensive review\nof the literature may provide additional information on the effect of\nexercise on EGR1 expression in neurons. <\/p>\n\n\n\n

Conclussion<\/strong><\/p>\n\n\n\n

   The expression of EGR1 can enhance synaptic plasticity in the brain,\nleading to improved cognitive function. Exercise is also a factor that can\ninfluence EGR1 expression.<\/p>\n\n\n\n

Acknowledgement <\/strong><\/p>\n\n\n\n

This research was supported by the Indonesian\nUniversity of Education and Padjadjaran University.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors declare\nthat they have no conflict of interest.<\/p>\n\n\n\n

Funding Support<\/strong><\/p>\n\n\n\n

This study does not receive any\nfunding from any type of institution.<\/p>\n\n\n\n

References <\/strong><\/p>\n\n\n\n

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