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Two Genes in Prefrontal Cortex Implicated in PTSD

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NEW YORK (Reuters Health) – A post-mortem analysis of brain tissue from people diagnosed with post-traumatic stress disorder (PTSD) revealed that two genes in the prefrontal cortex, ELFN1 and UBA7, play key roles in the condition, researchers say.

“ELFN1 is thought to play a role in a set of inhibitory (GABA-releasing) nerve cells that tune brain activity and help parts of the brain communicate effectively with each other. These cell types also play a role in stress response and in anxiety,” Dr. John Krystal of Yale School of Medicine in New Haven, told Reuters Health by email. UBA7 is expressed by activated microglia.

“The expression levels of both ELFN1 and UBA7 were decreased in PTSD,” he said, “raising the possibility of cortical disinhibition and compromise of microglial-related immune functions and their role in maintaining and disrupting synaptic connections.”

“However, we think it is unlikely that either gene causes PTSD on its own,” he noted. “We now know that these genes are associated with PTSD but we do not know how they are associated with PTSD.”

“Our study also revealed that PTSD molecular changes manifest differently between men and women,” added lead author Dr. Matthew Girgenti, also of Yale. “This suggests that a one-size-fits-all approach to treatment may not be appropriate. Future drug development may be needed to identify therapeutics specific for each sex.”

As reported in Nature Neuroscience, the researchers conducted differential gene expression and network analyses of four prefrontal cortex subregions of individuals with PTSD and integrated the findings with genotype data from the largest PTSD genome-wide association study.

As Dr. Krystal noted, they identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. ELFN1 expression also differed between men and women, which the authors suggest might help explain why women are more than twice as likely to develop PTSD and other anxiety disorders as men.

The team also compared molecular profiles between PTSD and other neurological disorders, and found that gene expression was more similar schizophrenia, autism and bipolar disorder than to depression.

Dr. Sachin Patel, Director, Division of General Psychiatry at Vanderbilt University Medical Center in Memphis, commented in an email to Reuters Health, “The key driver ELFN1, and potentially compensatory changes in SST and GAD2, identified in the study are important regulators of excitation and inhibition in the brain. This is particularly interesting as the most common first-line treatments for PTSD, such as (selective serotonin reuptake inhibitors), affect monoamine signaling; however newer treatment approaches are aimed at targeting GABAergic inhibitory transmission and excitatory glutamatergic transmission.”

“The study supports continued investigation of new neurotransmitter systems apart from serotonin as potential targets for PTSD therapeutics,” he said. “Learning more about the biology of ELFN1 and how it regulates brain circuit function in PTSD pathology may ultimately reveal new molecular targets for drug development.”

That said, he added, “As a field, we are pretty unified in our thinking that behavioral therapy (psychotherapy) combined with medications often yields the best results (for PTSD). Moreover, we know that behavioral therapy can change brain function. There is no doubt many types of evidence-based therapies are highly effective for many disorders, and the (study) does not negate any of this.”

Dr. Carole Lieberman, a psychiatrist in Beverly Hills and author of two books on PTSD, noted, “Many studies that focus on genetic or biological aspects of psychiatric disorders do a disservice to patients because they distract clinicians from psychosocial issues and treatment.”

With regard to PTSD, she said, “the most important psychosocial factors, in my experience, include: the psychological resilience a person has based upon childhood development, whether they have underlying psychological problems or mental illness, the magnitude of the trauma, their social support, and especially how soon they get intensive psychotherapy – and for how long.”

SOURCE: https://go.nature.com/34Zkxgo Nature Neuroscience, online December 21, 2020.

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