Neurochemical correlates of synapse density in a Huntington's disease mouse model.

Striatal medium spiny neurons are highly susceptible in Huntington's disease (HD), resulting in progressive synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1 H-MRS), are used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the association between brain neurochemical alterations and synaptic dysregulation remains unknown, limiting our ability to monitor potential treatments that may affect synapse function. We conducted in vivo longitudinal 1 H-MRS in the striatum followed by ex vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD, thalamo-striatal (T-S), and cortico-striatal (C-S) pathways, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175(Tg/0) HD mouse model as well as zQ175 mice lacking one allele of CK2α'(zQ175(Tg/0) :CK2α'(+/-) ), a kinase previously shown to regulate synapse function in HD. Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α'(+/-) . Changes in T-S and C-S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C-S synapse number positively correlated with 1 H-MRS-measured levels of GABA, while T-S synapse number positively correlated with levels of phosphoethanolamine and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by 1 H-MRS may facilitate monitoring circuit-specific synaptic dysfunction in the zQ175 mouse model and in other HD pre-clinical studies.

Adolescent reinforcement-learning trajectories predict cocaine-taking behaviors in adult male and female rats.

The anatomical, structural, and functional adaptations that occur in the brain during adolescence are thought to facilitate improvements in decision-making functions that are known to occur during this stage of development. The mechanisms that underlie these neural adaptations are not known, but deviations in developmental trajectories have been proposed to contribute to the emergence of mental illness, including addiction. Direct evidence supporting this hypothesis, however, has been limited. Here, we used a recently developed reversal-learning protocol to investigate the predictive relationship between adolescent decision-making trajectories and cocaine-taking behaviors in adulthood. Decision-making functions in the reversal-learning task were assessed throughout adolescence and into adulthood in male and female Long-Evans rats. Trial-by-trial choice data was fitted with a reinforcement-learning model to quantify the degree to which choice behavior of individual rats was influenced by rewarded (e.g., ∆+ parameter) and unrewarded (e.g., ∆0 parameter) outcomes. We report that reversal-learning performance improved during adolescence and that this was due to an increase in value updating for rewarded outcomes (e.g., ∆+ parameter). Furthermore, the rate of change in the ∆+ parameter predicted individual differences in the ∆+ parameter and, notably, cocaine-taking behaviors in adulthood: Rats that had a shallower adolescent trajectory were found to have a lower ∆+ parameter and greater cocaine self-administration in adulthood. These data indicate that adolescent development plays a critical role in drug use susceptibility. Future studies aimed at understanding the neurobiological mechanisms that underlie these age-related changes in decision-making could provide new insights into the biobehavioral mechanisms mediating addiction susceptibility.

Cushing's syndrome driver mutation disrupts protein kinase A allosteric network, altering both regulation and substrate specificity.

Genetic alterations in the PRKACA gene coding for the catalytic α subunit of the cAMP-dependent protein kinase A (PKA-C) are linked to cortisol-secreting adrenocortical adenomas, resulting in Cushing's syndrome. Among those, a single mutation (L205R) has been found in up to 67% of patients. Because the x-ray structures of the wild-type and mutant kinases are essentially identical, the mechanism explaining aberrant function of this mutant remains under active debate. Using NMR spectroscopy, thermodynamics, kinetic assays, and molecular dynamics simulations, we found that this single mutation causes global changes in the enzyme, disrupting the intramolecular allosteric network and eliciting losses in nucleotide/pseudo-substrate binding cooperativity. Remarkably, by rewiring its internal allosteric network, PKA-CL205R is able to bind and phosphorylate non-canonical substrates, explaining its changes in substrate specificity. Both the lack of regulation and change in substrate specificity reveal the complex role of this mutated kinase in the formation of cortisol-secreting adrenocortical adenomas.