Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9 pat ) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.

Two subpopulations of midbrain dopamine (DA) neurons are known to have different dynamic firing ranges in vitro that correspond to distinct projection targets: the originally identified conventional DA neurons project to the dorsal striatum and the lateral shell of the nucleus accumbens, whereas an atypical DA population with higher maximum firing frequencies projects to prefrontal regions and other limbic regions including the medial shell of nucleus accumbens. Using a computational model, we show that previously identified differences in biophysical properties do not fully account for the larger dynamic range of the atypical population and predict that the major difference is that originally identified conventional cells have larger occupancy of voltage-gated sodium channels in a long-term inactivated state that recovers slowly; stronger sodium and potassium conductances during action potential firing are also predicted for the conventional compared to the atypical DA population. These differences in sodium channel gating imply that longer intervals between spikes are required in the conventional population for full recovery from long-term inactivation induced by the preceding spike, hence the lower maximum frequency. These same differences can also change the bifurcation structure to account for distinct modes of entry into depolarization block: abrupt versus gradual. The model predicted that in cells that have entered depolarization block, it is much more likely that an additional depolarization can evoke an action potential in conventional DA population. New experiments comparing lateral to medial shell projecting neurons confirmed this model prediction, with implications for differential synaptic integration in the two populations.

Inhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β -subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon-and midbrain dopamine neuron-specific deletion of an A-type K + channel β -subunit leads to a selective gain of function in extinction learning. One Sentence Summary:Exon-and midbrain dopamine neuron-specific deletion of the Kv4 channel β -subunit KChIP4a selectively accelerates extinction learning

Background: Although practice guidelines stress individualization of glucose management in patients with type 2 diabetes (T2D), the extent to which providers take patient factors into account when selecting medications is not well known. We used data from DCR to evaluate the current real-world landscape of glucose-lowering drugs in key subsets of patients with T2D. Methods: DCR is the first large-scale US outpatient registry of patients with diabetes recruited from cardiology, endocrinology, and primary care practices and currently encompasses 374 practices and 5114 providers. T2D medications were grouped as those which are suboptimal for patients with 1) obesity: insulin, sulfonylurea, TZD; 2) elderly (i.e., high hypoglycemia risk): insulin, sulfonylurea; 3) CKD 4/5: metformin, sulfonylurea; and 4) CV disease: sulfonylurea. We examined patient factors associated with use of these groups of meds using 4 hierarchical (for both specialty and site) modified Poisson models, adjusting for HbA1c, number of T2D meds, and insurance. Results: Overall, 157,551 patients with T2D were prescribed a med for glycemic control: metformin 75%, sulfonylurea 34%, insulin 28%, DPP-4i 18%, TZD 11%, GLP-1 RA 6.4%, SGLT2i 4.8%. After adjusting patient factors, glycemic control, and insurance status, patients with higher BMIs were more likely treated with medications prone to cause weight gain (obesity class I/II: rate ratio [RR] 1.02, 95% CI 1.00-1.03; obesity class III: RR 1.09, 95% CI 1.05-1.12). Older patients were more likely to be treated with meds with increased risk of hypoglycemia (RR 1.04 per 5 years, 95% CI 1.03-1.05). Patients with GFR <30 were less likely to be treated with meds with known risk in patients with CKD (RR 0.72, 95% CI 0.68-0.76). Patients with CAD were less likely to be treated with meds with known CV harm (RR 0.97, 95% CI 0.96-1.00). Conclusion: In a large US-based registry of T2D patients, we observed some targeted use of glucose-lowering therapy—in particular, patients with advanced CKD and CAD were not given meds known to be harmful to these patients. However, risk of hypoglycemia and risk of weight gain did not appear to factor substantially into decision making. As these are among several factors that go into drug selection for complicated patients with T2D, conclusions from these data are limited. Nonetheless, in an era of increasing number and complexity of medication choices with varying risk/benefits, databases like the DCR may allow investigators to assess these trends and to highlight potential areas for improvement in pharmacologic personalization, particularly as the use of newer drug classes grows.