Human gene variant in ADHD, autism exposes sex-dependent neural signaling mechanisms

Human gene variant in ADHD, autism exposes sex-dependent neural signaling mechanisms

The prevalence, age of onset, and clinical symptoms of virtually all neuropsychiatric disorders differ between men and women. Disorders with a pronounced gender bias include attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), where the ratio of males to females diagnosed is approximately 4 to 1. If this biased ratio derives from roles played in brain development by sex-specific DNA sequences or hormones or reflects how biological mechanisms and environmental influences elicit different behavioral patterns in males and females, remains an area of ​​research. open investigation.

Regardless of their origin, altered behavior in these disorders signals a change in the function of key brain circuits hardwired during development, refined throughout life, and coordinated by the actions of brain chemicals called neurotransmitters. A vital neurotransmitter that plays a key role in behaviors altered by both ADHD and ASD is dopamine, whose powerful actions support motor initiation and coordination, motivation, reward and social behavior, as well as attention and higher cognitive function. Although the dopamine-sensitive brain circuits engaged in these processes have been under surveillance for decades and, in the case of ADHD, are the target of drugs such as Adderall® and Ritalin®, intrinsic sex-dependent differences in these pathways that could further guide precise diagnoses and treatments have only recently begun to be elucidated.

To better understand how dopamine levels at brain synapses are managed, neuroscientists from Florida Atlantic University, along with collaborators from the University of North Dakota School of Medicine and Health Sciences, have now added an important piece to this puzzle by establishing key differences in the molecular system. dopamine elimination machinery in the brains of male and female mice.

The new research published in the journal Molecular psychiatry and led by Randy Blakely, Ph.D., professor of biomedical sciences at FAU’s Schmidt College of Medicine and executive director of the FAU Stiles-Nicholson Brain Institute, provides new insight into how gender determines the mechanisms by which Distinct synapses monitor and regulate dopamine signaling. Moreover, the impact of the sex differences described is particularly pronounced when the mice express a human genetic variant found in boys with ADHD or ASD.

“Often, due to assumptions that varying sex hormones will cloud interpretations of the data and that using one sex will halve animal use and costs without loss of key information, many researchers using animal models to study brain disorders work primarily with males, even more reasonable when modeling disorders that exhibit male bias,” Blakely said.

In a previous study, looking for genetic changes in dopamine regulatory genes in children with ADHD, Blakely and his team identified a genetic variant that alters the function of the dopamine transporter (DAT) in a way particular. Normally, DAT acts to remove dopamine from synapses, acting as a nanoscale dopamine vacuum. When the DAT variant was expressed in cells, however, it “recoiled”, spitting out dopamine rather than effectively eliminating it. After engineering the variant into the mouse genome, Blakely’s team found changes in behavior and drug responses predicted by this abnormal DAT behavior, with a focus on traits related to pathways related to locomotor activation, habitual behavior and impulsivity. In particular, these studies were carried out exclusively with male mutant mice.

Blakely and Adele Stewart, Ph.D., the report’s first author, an assistant research professor of biomedical sciences at FAU’s Schmidt College of Medicine and a member of the FAU Stiles-Nicholson Brain Institute, agreed there was more to be done. , especially regarding how females would handle the mutation. Would the DAT mutation have an impact on the same brain regions and the same behaviors in women as in men? The answer is a definite no. Females show effects of the mutation in unaffected brain regions in males and vice versa. Other work has found that this switch is due to a circuit flip in how brain pathways in both men and women use a key regulatory protein DAT to amplify reverse transporter activity.

The behavioral consequences of this region-specific, sex-biased pattern of DAT regulation are profound, with mutant DAT altering behaviors in a unique pattern for each sex. For example, mutant females appeared to be more anxious and had novelty recognition issues compared to wild-type females. Males, on the other hand, are less social and display increased persevering behavior, changes not seen in females.

“Our work clearly shows that female mutant DAT mice are not ‘protected’ from the impact of the mutation, but rather exhibit a unique set of behavioral changes related to an ingrained and sex-biased architecture of the dopaminergic system,” Stewart said. . “The same variant was also found in two unrelated boys with ASD, a disorder that often also displays comorbid ADHD.”

Interestingly, the only reported clinical occurrence of the DAT variant in a female involved a diagnosis of bipolar disorder (BPD). It has been suggested that the mania and depression associated with borderline personality disorder are linked to impaired dopamine signaling. Blakely’s group also reported elevated impulsivity traits in a female carrier of the same mutation studied in this latest paper, suggesting that an overlap of dopamine-related traits may also occur between genders, or perhaps that forms of impulsivity (eg, waiting or acting) may be involved.

A “resilience” framework is often used to explain the discrepancies in gender bias observed in neuropsychiatric disorders. However, recent evidence suggests that sex bias may be due, at least in part, to differences in symptomology and associated comorbidities and the resulting failure of current diagnostic instruments to ensure identification of the same disorder in both. sexes.

“While we understand that there are biological differences between rodent and human brains, studies like ours provide an important opportunity to explore the biological mechanisms that contribute to sex differences in the risk of neuropsychiatric diseases.” , Stewart said. “What our study shows is that behavioral generalizations between genders can limit the diagnosis of mental illness, particularly if one gender translates alterations in outward signs such as hyperactivity and aggression over manifestations more internal ones such as learning, memory, and mood, even when the same Moreover, our work supports the idea that treatment strategies need to take into account the sex-dependence of neural signaling mechanisms rather than assuming that what’s good for the goose is good for the gander. The therapies may either not be good for the gander at all, or may be good for a completely different type of disorder.”

The research provides a clear example of how genetic changes can have sex-dependent effects on physiology and behavior, depending on whether other coregulatory genes are naturally expressed by the same cells.

“Because the basis of the differential response to the DAT mutation is the presence or absence of DAT regulation in these two domains, the implications do not apply only to the few individuals carrying the genetic variant nor are they limited to ADHD. and the TSA,” Blakely said. . “Investigators exploring other disorders related to altered dopamine signaling should consider whether the mechanism we discovered could drive sex-dependent features of these diseases. By extension, we now need to determine whether the mechanism we have discovered contributes to sex-dependent ways in which dopamine signaling drives normal behavior.”

Source:

Florida Atlantic University

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