Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner.

Serotonin 2A receptors (5-HT Rs) mediate the effects of psychedelic drugs. 5-HT R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT Rs control the HTR.

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.

Influence of Schizophrenia-Associated Gene Egr3 on Sleep Behavior and Circadian Rhythms in Mice.

Up to 80% of people meeting DSM-IV definitions for schizophrenia will exhibit difficulties with sleep, along with a breakdown in circadian entrainment and rhythmicity. The changes to the sleep and circadian systems in this population are thought to be interdependent, as evidenced by the frequent use of the combined term "sleep and circadian rhythm disruption" or "SCRD" to describe their occurrence. To understand links between sleep and circadian problems in the schizophrenia population, we analyzed the duration and rhythmicity of sleep behavior in mice lacking function of the immediate early gene early growth response 3 ( Egr3).

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.

Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder.

Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders.

Attenuated Late-Phase Transcription in the Dentate Gyrus of Mice Lacking .

The dentate gyrus (DG) engages in sustained transcription for at least 8 hours following behavioral induction, and this time course may be functionally coupled to the unique role of the DG in hippocampus-dependent learning and memory. The factors that regulate long-term DG expression, however, remain poorly understood. Animals lacking show less expression following convulsive stimulation, but the effect of ablation on behaviorally induced remains unknown.

Nab2 maintains thymus cellularity with aging and stress.

Thymic cellularity is influenced by a variety of biological and environmental factors, such as age and stress; however, little is known about the molecular genetic mechanisms that regulate this process. Immediate early genes of the Early growth response (Egr) family have critical roles in immune function and response to environmental stress. The transcription factors, Egr1, Egr2 and Egr3, play roles in the thymus and in peripheral T-cell activation.

Sleep Homeostatic and Waking Behavioral Phenotypes in -Deficient Mice Associated with Serotonin Receptor 5-HT Deficits.

Study Objective: The expression of the immediate early gene early growth response 3 () is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep.

Methods: Electroencephalogram/electromyogram (EEG/EMG) were recorded in -/- and wild-type (WT) mice during 24 h baseline, 6 h sleep disruption and 6 h recovery.

Distinct dendritic morphology across the blades of the rodent dentate gyrus.

The dentate gyrus (DG) is a hippocampal region that has long been characterized as a critical mediator of enduring memory formation and retrieval. As such, there is a wealth of studies investigating this area. Most of these studies have either treated the DG as a homogeneous structure, or examined differences in neurons along the septal-temporal axis.

Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis.

Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the α-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ.

Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner.

Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor.

HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity.

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown.

Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine.

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine.

Family-based association study of early growth response gene 3 with child bipolar I disorder.

Background: The risk for relapse of child bipolar I disorder (BP-I) is highly correlated with environmental factors. Immediate early genes of the early growth response (EGR) gene family are activated at high levels in the brain in response to environmental events, including stress, and mediate numerous neurobiological processes that have been associated with mental illness risk. The objective of this study is to evaluate whether single nucleotide polymorphisms (SNPs) in EGR genes are associated with the risk to develop child bipolar I disorder.