A variant of the human gene in ADHD, autism exposes the sex addiction of neuronal signaling mechanisms

The prevalence, age of onset, and clinical symptoms of nearly all neuropsychiatric disorders differ between men and women. Among the disorders with pronounced sexual bias are Attention Deficit / Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), in which the diagnosed male / female ratio is approximately 4 to 1. If this distorted ratio arises by the roles played in brain development by sex-specific DNA or hormone sequences or reflecting how biological mechanisms and environmental influences elicit behavioral patterns differently in males and females, remains an open area of ​​investigation.

Regardless of the origin, the altered behavior in these disorders signals a change in the function of key brain circuits connected during development, refined throughout life and coordinated through the action of brain chemicals called neurotransmitters. A vital neurotransmitter that plays a key role in altered behaviors from both ADHD and ASD is dopamine, whose powerful actions support motor initiation and coordination, motivation, reward and social behavior, as well as attention. and superior cognitive function. Although the dopamine-sensitive brain circuits involved in these processes have been examined 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 could drive more precise diagnoses and treatments have only recently begun to be clarified.

To better understand how dopamine levels in 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 a significant piece to this puzzle by establishing key differences. in the dopamine disposal 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 insights into how sex determines the mechanisms by which distinct synapses monitor and they regulate dopamine signaling. Furthermore, the impact of the sex differences described is particularly pronounced when mice express a human genetic variant found in boys with ADHD or ASD.

Often, due to the assumption that variation in sex hormones blurs data interpretations and that the use of one sex will cut animal use and costs in half without a loss of key information, many researchers use animal models to study brain disorders work primarily with males, even more reasonable when modeling disorders that exhibit male bias. “

Randy Blakely, Ph.D., Professor of Biomedical Sciences, FAU’s Schmidt College of Medicine

In a previous study, looking for genetic changes in dopamine regulatory genes in children with ADHD, Blakely and his team identified a gene variant that alters dopamine transporter (DAT) function in a particular way. Normally DAT acts to remove dopamine from synapses, acting like a dopamine vacuum cleaner at the nanoscale. When the DAT variant was expressed in cells, however, it ‘ran backwards’, spitting out dopamine rather than efficiently removing it. After engineering the variant in the mouse genome, Blakely’s team discovered the changes in behavior and drug responses predicted by this abnormal DAT behavior, with an emphasis on traits related to pathways related to locomotor activation, behavior habitual and impulsive. Notably, these studies were performed exclusively with male mutant mice.

Blakely and Adele Stewart, Ph.D., first author of the report, assistant professor of biomedical sciences at FAU’s Schmidt College of Medicine and member of the FAU Stiles-Nicholson Brain Institute, acknowledged that there was still a lot to do, particularly compared to how females would manage the mutation. Would the DAT mutation impact the same brain regions and behaviors in females as it did in males? The answer is a resounding no. Females show the effects of the mutation in unaffected brain regions in males and vice versa. Further work revealed that this switch is due to a circuit flip in the way brain pathways in males and females use a key DAT regulatory protein to amplify the backward activity of the transporter.

The behavioral consequences of this region-specific, sex-linked DAT regulatory pattern are profound, with mutant DAT altering behaviors in a unique pattern for each sex. For example, mutant females seemed more anxious and had problems with novelty recognition than wild-type females. Males, on the other hand, are less sociable and exhibit 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 entrenched and sex-part architecture of the dopamine system,” Stewart said. “The same variant was also found in two unrelated boys with ASD, a disorder that often also shows comorbidity of ADHD.”

Interestingly, the only reported clinical event of the DAT variant in a woman resulted in a diagnosis of bipolar disorder (BPD). It has been suggested that both mania and depression associated with BPD are linked to impaired dopamine signaling. Blakely’s group also reported high impulsivity traits in a female carrying the same mutation studied in this latest article, suggesting that overlapping of dopamine-related traits may also occur between genders, or perhaps forms of impulsivity (eg. wait versus action) may be involved.

A “resilience” picture is often used to explain the discrepancies in sexual bias seen in neuropsychiatric disorders. However, recent evidence suggests that sexual bias may be due, at least in part, to differences in associated symptoms and comorbidities and the consequent failure of current diagnostic tools to ensure identification of the same disorder in both sexes.

“While we understand that there are biological differences between rodents and human brains, studies like ours provide an important opportunity to explore the biological mechanisms that contribute to sex differences in neuropsychiatric disease risk,” said Stewart. “What our study shows is that behavioral generalizations between genders can limit the diagnosis of mental illness, particularly if a sex translates the alterations into outward signs such as hyperactivity and aggression versus more internal manifestations such as learning, memory and mood. even when the disease itself is at work. Furthermore, our work supports the idea that treatment strategies should be aware of the sex-dependent neuronal signaling mechanisms rather than assuming that the treatment that is good for the goose is good for the male. be good for the male or good for a completely different kind of ailment. “

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

“Since the basis for the differential response to the DAT mutation is the presence or absence of DAT regulation in these two areas, the implications do not apply only to the few individuals with the genetic variant nor are they limited to ADHD and ASD,” he said. Blakely. Investigators exploring other disorders related to impaired dopamine signaling should consider whether the mechanism we discovered could drive the sex-dependent characteristics of these diseases. By extension, we now need to consider whether the mechanism we discovered contributes to sex-dependent modes in where dopamine signaling drives normal behavior. “


Florida Atlantic University

Journal reference:

Stewart, A., et al. (2022) Abnormal and behavioral penetrating dopamine efflux exposes sex-dependent and circuit-dependent regulation of dopamine transporters. Molecular Psychiatry. doi.org/10.1038/s41380-022-01773-7.


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