Biology subjects

Mayer, F. P.

Publications and source records attributed to Mayer, F. P..

3 recordsLinked to original sources

bioRxiv2023

Kappa Opioid Receptor Antagonism Rescues Genetic Perturbation of Dopamine Homeostasis: Molecular, Physiological and Behavioral Consequences

Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate, as exemplified by the therapeutic use of d-amphetamine and methylphenidate for the treatment of ADHD, agents with high abuse liability. In search for an improved and non-addictive therapeutic approach for the treatment of DA-linked disorders, we utilized a preclinical mouse model expressing the human DA transporter (DAT) coding variant DAT Val559, previously identified in individuals with ADHD, ASD, or BPD. DAT Val559, like several other disease-associated variants of DAT, exhibits anomalous DA efflux (ADE) that can be blocked by d-amphetamine and methylphenidate. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might also provide an alternative approach to normalizing DA-signaling disrupted by perturbed DAT function. Here we demonstrate that KOR stimulation leads to enhanced surface trafficking and phosphorylation of Thr53 in wildtype DAT, effects achieved constitutively by the Val559 mutant. Moreover, these effects can be rescued by KOR antagonism of DAT Val559 in ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release as well as sex-dependent behavioral abnormalities observed in DAT Val559 mice. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.

neuroscience↗

bioRxiv2022

DAT Val559 Mice Exhibit Compulsive Behavior Under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose-poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pairwise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors.

neuroscience↗

bioRxiv2021

Sex and Circuit Specific Dopamine Transporter Regulation Underlies Unique Behavioral Trajectories of Functional SLC6A3 Coding Variation

Virtually all neuropsychiatric disorders display sex differences in prevalence, age of onset, and/or clinical symptomology. In sex-biased disorders, one sex is often suggested to harbor protective mechanisms, rendering them resilient to genetic and/or environmental risk factors. Here, we demonstrate sex-biased molecular, pharmacological and behavioral effects induced by the dopamine (DA) transporter (DAT) coding variant Ala559Val, previously identified in subjects diagnosed with the male-biased disorders attention-deficit/hyperactivity disorder and autism spectrum spectrum disorder. In DAT Val559 mice, we identified sex differences in response to psychostimulants, social behavior, and cognitive traits. We reveal a sex by circuit dissociation in D2-type autoreceptor (D2AR) regulation of DAT wherein D2AR-dependent DAT phosphorylation and trafficking, detectable in the male dorsal striatum, does not occur in females but rather is a property of the ventral striatum, predicting sex-specific changes in behavior. Consequently, we found that a subset of altered behaviors can be normalized using the D2R antagonist sulpiride in DAT Val559 mice. Our studies provide a cogent example of how sex shapes the behavioral trajectory of DA signaling perturbations and identify the sex-dependent, locality-selective capacity for D2AR regulation of DAT as an unrecognized determinant of this trajectory. Rather than identifying one sex as resilient, we find that sex can drive alterative behavioral patterns from shared signaling perturbations that may result in females being underreported. Our work underscores the utility of model systems to study the functional intrusions of rare genetic variation to gain insights into pathways underlying normal and perturbed trait domains associated with common neuropsychiatric conditions.

neuroscience↗