Editorial: the role of immediate early genes in neuropsychiatric illness

Editorial on the Research Topic
The Role of Immediate Early Genes in Neuropsychiatric Illness

The field of psychiatry lags behind other areas of medicine in not yet having identified a single gene that causes a mental illness (excluding neuro-developmental or neurodegenerative disorders such as autism spectrum disorders or dementias). This is due to the “ complex genetics” that underlie these disorders. Specifically, many genetic variations across the genome influence risk for neuropsychiatric illnesses, no single one of which is responsible for a large percentage of cases, and non-genomic factors play a major role in their development. Together, these form the two major challenges that the field of psychiatry faces to identify the causes of mental health disorders: (1) how so many genes can influence risk for these illnesses, and (2) how environment interacts with predisposing genetic variations to result in neuropsychiatric illness.

A category of genes called immediate early genes (IEGs) are poised to answer both of these questions. IEGs are rapidly activated in the brain in response to neuronal activity which, itself, is triggered by environmental events. Many IEGs encode transcription factors, which regulate an array of target genes that carry out the cellular response to the stimulus. Thus, IEGs are positioned at the nexus between environmental stimuli, and the molecular events that can dictate long-term changes in the brain, including processes such as synaptic plasticity and memory formation. From this position, IEGs may determine both the “ gene-environment” and “ multiple-gene” influences on risk to develop psychiatric illness. The research, review, and hypothesis articles comprising this Research Topic explore “ The Role of Immediate Early Genes in Neuropsychiatric Illness.”

One of the leading categories of environmental factors that increase risk for neuropsychiatric illnesses is stress. This term encompasses events ranging from in utero exposure to famine or infection, to stressful life events. Stress also activates expression of IEGs. In their Hypothesis/Review, Marballi and Gallitano describe the cascade of proteins activated in neurons in response to stress that culminate in expression of Egr3 , a member of the Early Growth Response ( Egr ) family of IEG transcription factors. This stress-responsive “ biological pathway” is essential for memory formation and synaptic plasticity. They point out that numerous genes encoding the proteins in this pathway have been associated with risk for schizophrenia, and present a model to explain how this pathway may represent a neuroprotective response to stress. Thus, variations that result in an insufficient activation of this protective stress-responsive pathway may result in the neuropathology that gives rise neuropsychiatric illness in individuals exposed to stress. However, an individual carrying the same susceptibility variations who is not exposed to significant stressors may not develop illness.

Once activated, IEGs mediate processes such as growth factor regulation, myelination, vascularization, synaptic plasticity, and memory and cognition. Notably, dysfunction in each of these areas has been implicated in mental illness pathogenesis. Two papers in the Research Topic address interactions between Egr3 and the critical growth factor brain-derived neurotrophic factor (BDNF). In their review article, Pfaffenseller et al. integrate results from their group and others, showing that peripheral BDNF levels are reduced in patients experience mood disorders, with their recent findings indicating that Egr3 is a master regulator of genes that are reduced in the prefrontal cortex of bipolar disorder patients. Prior studies showing that Egr3 is activated downstream of BDNF, and suggesting that BDNF may play a beneficial role in bipolar disorder, lead them to propose a “ feed-forward” model in which both BDNF and Egr3 play protective roles, and are reduced in bipolar disorder.

The second of these articles reports the novel research finding that Egr3 is required for the induction of hippocampal BDNF expression in response to electroconvulsive seizure, a known stimulus of BDNF expression Meyers et al. These results suggest that Egr3 may regulate activity-dependent expression of BDNF, and support the model of a feed-forward pathway proposed by Pfaffenseller et al. but providing the evidence that Egr3 is acting upstream, in addition to being activated downstream, of BDNF. The results of Meyers et al. provide a mechanism to suggest how dysfunction of Egr3 may result in the BDNF deficiency found in bipolar disorder.

Other articles in the Research Topic address the role of IEGs in reward circuitry and addictive disorders. Manning et al. examine the role that IEGs play in stress-dependent remodeling of neural circuits involved in reward. Changes in the circuitry linking brain regions involved in pleasure, motivation, memory, decision-making and behavior is thought to influence mood disorders as well as addictive behaviors. After describing the cortico-basal ganglia reward network, they review the stress-responsive expression, and evidence for potential contributions to mood and addictive disorders, of a range of IEGs: CREB, SRF, Egr1, Arc, NPAS4, Homer1a , and the AP-1 Proteins c-fos, FosB/ΔFosB, and Jun. They conclude by posing key questions about the roles of IEGs that must be answered to advance our understanding of how these important genes may be influencing neuropsychiatric illnesses.

In their review article, Chandra and Lobo make the important point that IEGs are not simply markers of neuronal activity in response to processes but, in fact, play essential roles in the neurobiology underlying them. They focus on findings indicating that specific IEGs expressed in subsets of neurons in the striatum mediate cellular and molecular processes influencing plasticity and behavior that may mediate addiction to psychostimulants. The reviewed studies have relevance to neuropsychiatric disorders characterized by dysfunction in reward-seeking behaviors and motivational states as well as habitual behaviors.

In their research article, Muñiz et al. examine the role that caffeine plays in potentiating the effects of cocaine on reward-related learning in mice. They examined the expression of IEGs and dopamine receptor (DAR) subtypes in animals learning to associate a novel environment with drug exposure in the conditioned place preference paradigm. Their findings show that the combination of cocaine plus caffeine induced a set of IEG and DAR subtypes in the nucleus accumbens and prefrontal cortex that differ from the genes activated in response to cocaine alone. Their finding suggests that caffeine, the most widely used psychostimulant worldwide, may potentiate the effect of cocaine in reward-related memory formation.

Another group of articles address the contribution of IEGs to processes of learning and memory. Many IEGs have essential functions in memory formation and regulation of synaptic plasticity. Thus, defects in the functioning of IEGs could contribute to the cognitive symptoms characteristic of many neuropsychiatric illnesses. Duclot and Kabbaj provide a comprehensive review of the roles of a single IEG, Egr1 , in the central nervous system. Egr1 is an IEG transcription factor required for memory reconsolidation and the late phase of long-term potentiation (LTP), a form of synaptic plasticity ( Jones et al., 2001 ). The authors systematically review the upstream processes that activate Egr1 , as well as the downstream genes, pathways, and biological functions of Egr1 . They conclude with a discussion of the role of Egr1 in neuronal physiology, and how its dysfunction may contribute to neurological and psychiatric disorders.

In their review article, Gallo et al. address the critical role of numerous IEGs in learning, memory, and synaptic plasticity, pointing out how deficiencies in these processes may underlie the cognitive deficits characteristic of neuropsychiatric disorders. They expand their focus on Egr1 to including the additional IEGs c-fos and Arc , covering the molecular actions of these genes in brain and their roles in learning and memory. With this framework, they then discuss the potential contribution that these IEGs may make in neuropsychiatric disorders ranging from mood disorders, to PTSD, to schizophrenia.

Jones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T. V., Garel, S., et al. (2001). A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–96. doi: 10. 1038/85138

Ramaker, R. C., Bowling, K. M., Lasseigne, B. N., Hagenauer, M. H., Hardigan, A. A., Davis, N. S., et al. (2017). Post-mortem molecular profiling of three psychiatric disorders. Genome Med. 9: 72. doi: 10. 1186/s13073-017-0458-5