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Environmental Stimuli Activates Early Growth Response 3 (EGR3), an Immediate Early Gene Residing at the Center of a Biological Pathway Associated with Risk for Schizophrenia

Description

Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced

Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced over the past few years, high economic burdens are still conferred to society, totaling more than $34 billion in direct annual costs to the United States of America. Thus, a critical need exists to identify the factors that contribute towards the etiology of schizophrenia. This research aimed to determine the interactions between environmental factors and genetics in the etiology of schizophrenia. Specifically, this research shows that the immediate early gene, early growth response 3 (EGR3), which is upregulated in response to neuronal activity, resides at the center of a biological pathway to confer risk for schizophrenia. While schizophrenia-risk proteins including neuregulin 1 (NRG1) and N-methyl-D-aspartate receptors (NMDAR’s) have been identified upstream of EGR3, the downstream targets of EGR3 remain relatively unknown. This research demonstrates that early growth response 3 regulates the expression of the serotonin 2A-receptor (5HT2AR) in the frontal cortex following the physiologic stimulus, sleep deprivation. This effect is translated to the level of protein as 8 hours of sleep-deprivation results in the upregulation of 5HT2ARs, a target of antipsychotic medications. Additional downstream targets were identified following maximal upregulation of EGR3 through electroconvulsive stimulation (ECS). Both brain-derived neurotrophic factor (BDNF) and its epigenetic regulator, growth arrest DNA-damage-inducible 45 beta (GADD45B) are upregulated one-hour following ECS in the hippocampus and require the presence of EGR3. These proteins play important roles in both cellular proliferation and dendritic structural changes. Next, the effects of ECS on downstream neurobiological processes, hippocampal cellular proliferation and dendritic structural changes were examined. Following ECS, hippocampal cellular proliferationwas increased, and dendritic structural changes were observed in both wild-type and early growth response 3 knock-out (Egr3-/-) mice. Effects in the number of dendritic spines and dendritic complexity following ECS were not found to require EGR3. Collectively, these results demonstrate that neuronal activity leads to the regulation of schizophrenia risk proteins by EGR3 and point to a possible molecular mechanism contributing risk for schizophrenia.

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Date Created
  • 2020

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Cellular mechanisms underlying the effects of repeated D₂-like agonist treatment on prepulse Inhibition

Description

Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is

Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia.

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Date Created
  • 2013