Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia

Abstract

While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the “Index single nucleotide polymorphism (SNP)” (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in insufficient electrophysiologic, immunologic, and neuroprotective, processes that these genes normally mediate. Continued adverse environmental experiences, over time, may thereby result in neuropathology that gives rise to the symptoms of schizophrenia. By combining multiple genes associated with schizophrenia susceptibility, in a functional cascade triggered by neuronal activity, the proposed biological pathway provides an explanation for both the polygenic and environmental influences that determine the complex etiology of this mental illness.

Porcine placental extract facilitates memory and learning in aged mice

“…Four genes were significantly up‐regulated in aged mice treated with SD‐F relative to control, that is, Erg1 , Gadd45b , Nab2 , and Vegfa . These show different cellular localizations; Erg1 and Nab2 are localized in the cell nucleus, Gadd45b is localized to the cytoplasm, and Vegfa is secreted extracellularly (Gallo, Katche, Morici, Medina, & Weisstaub, ; Leach et al, ; Marballi & Gallitano, ; Mateo et al, ). Erg1 is a member of the Erg family of immediate early gene transcription factors and plays an important role in long‐term memory formation and late‐phase long‐term potentiation (LTP) (Cole, Saffen, Baraban, & Worley, ; Worley et al, ).…”

“…and Nab2 are localized in the cell nucleus, Gadd45b is localized to the cytoplasm, and Vegfa is secreted extracellularly (Gallo, Katche, Morici, Medina, & Weisstaub, 2018;Leach et al, 2012 Marballi & Gallitano, 2018;Mateo et al, 2006). Erg1 is a member of the Erg family of immediate early gene transcription factors and plays an important role in long-term memory formation and late-phase long-term potentiation (LTP) (Cole, Saffen, Baraban, & Worley, 1989;Worley et al, 1993).…”

Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae

“…The other branches of Ca 2+ signaling depend on voltage-gated calcium channels and receptor-operated channels. Among receptor-operated channels that are the best characterized and have been shown to interact with SOCE components are glutamate receptors, α-amino-3-hydroxy-5-methyl-4-iso-xazolepropionic acid receptors [ 12 ], and N -methyl-D-aspartate receptors [ 13 ]. These receptors are highly expressed in neuronal cells where they support neuronal excitability, synaptic plasticity, and neurotransmitter release [ 1 , 14 , 15 , 16 , 17 , 18 ].…”

“…Store-operated calcium entry has been shown to participate in the regulation of other Ca 2+ signaling pathways (reviewed in [ 9 , 19 ]), including the regulation of such transcriptional networks as the calcineurin/nuclear factor of the activated T-cell signaling cascade, nuclear factor κB [ 20 ], Sp4 [ 21 ], and adapter protein-1 [ 22 ]. Thus, neuronal SOCE can participate in the regulation of neurodevelopmental processes and cell fate via specific transcriptional programs of c- fos , neuronal PAS domain-containing protein-4 , and endothelial growth factor-1 transcription factors, also known as immediate early genes [ 13 , 23 , 24 , 25 , 26 ]. Moreover, the dysregulation of SOCE was shown to be involved in neurodegenerative diseases and other pathologies of the central nervous system (reviewed in [ 1 , 9 ]).…”

Sleep deprivation rapidly upregulates serotonin 2A receptor expression via the immediate early gene Egr3

“…Egr3 is one of four transcription factors (Egr1-4) in the Early Growth Response family of immediate early genes. The family also includes the immediate early gene Nab2, which encodes a co-regulator that binds to Egr1, 2, and 3, to co-regulate downstream genes, including the Egrs themselves, completing regulatory feedback interactions among the family members (31,32).…”