Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia.

Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer's disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice.

Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3.

Serotonin 2A receptors (5-HTRs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HTRs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HTRs are reduced in the brains of individuals with schizophrenia.

Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome.

Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly impacting females. MECP2 is an epigenetic transcriptional regulator acting mainly to repress gene expression, though it plays multiple gene regulatory roles and has distinct molecular targets across different cell types and specific developmental stages. In this review, we summarize MECP2 loss-of-function associated transcriptome and proteome disruptions, delving deeper into the latter which have been comparatively severely understudied.

The Immediate Early Gene Is Required for Hippocampal Induction of by Electroconvulsive Stimulation.

Early growth response 3 () is an immediate early gene (IEG) that is regulated downstream of a cascade of genes associated with risk for psychiatric disorders, and dysfunction of itself has been implicated in schizophrenia, bipolar disorder, and depression. As an activity-dependent transcription factor, EGR3 is poised to regulate the neuronal expression of target genes in response to environmental events. In the current study, we sought to identify a downstream target of EGR3 with the goal of further elucidating genes in this biological pathway relevant for psychiatric illness risk.

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

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.

Metabolomic profiling of schizophrenia patients at risk for metabolic syndrome.

Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia. However, SGAs cause metabolic disturbances that can manifest as metabolic syndrome (MetS) in a subset of patients. The causes for these metabolic disturbances remain unclear.

Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches.

Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation.

Differential neuregulin 1 cleavage in the prefrontal cortex and hippocampus in schizophrenia and bipolar disorder: preliminary findings.

Background: Neuregulin 1 (NRG1) is a key candidate susceptibility gene for both schizophrenia (SCZ) and bipolar disorder (BPD). The function of the NRG1 transmembrane proteins is regulated by cleavage. Alteration of membrane bound-NRG1 cleavage has been previously shown to be associated with behavioral impairments in mouse models lacking expression of NRG1-cleavage enzymes such as BACE1 and gamma secretase.

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation.

Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation.