Widening the scope of intensive treatment for PTSD in the military health system.

Recent trends have exacerbated existing problems accessing mental health care for military service members. To address these problems, lawmakers and military leaders have been busy introducing new legislation and changing policies in order to improve access. While these initiatives are critical for long-term change, military service members need solutions that can help them now. Although it may not be a panacea, intensive outpatient treatments may be part of the solution for the MHS, especially when considering posttraumatic stress disorder (PTSD). This commentary begins by describing the history of intensive treatments in the military health system, which has been largely offered as intensive outpatient treatments (IOPs). Next, it describes a decade of research on intensive treatments for PTSD, which has included a diverse array of IOP formats as well as stand-alone, massed treatments. Lastly, this commentary recommends that lawmakers and military leaders expand their notion of intensive outpatient treatments to include both programs and stand-alone, massed treatments. By doing so, the MHS could have more options for service members and commands as they search for workable treatment options.

Evaluation of outcomes for military mental health partial hospitalization program.

In the military health system, there has been a growing demand for mental health services over the last two decades. Partial hospitalization programs fill a critical niche between outpatient and inpatient services. The present study evaluated immediate and long-term outcomes of a military mental health partial hospitalization program at a large military treatment facility. This study collected retrospective data of active duty patients who completed a 6-day partial hospitalization program within a 2-year period. Results showed that the majority of participants were young, male, and junior enlisted service members endorsing suicidal ideation as well as adjustment/stressor- and depressive-related psychiatric symptoms. Immediately after treatment, participants showed a significant reduction in psychiatric symptoms and dysfunction after treatment. In the long-term, most participants engaged in mental health services post-discharge, though engagement with services decreased over time. In addition, career-impacting medical recommendations were made for over half of participants with almost three-quarters of these recommendations made before or during enrollment in the program. This study expanded the limited evidence base for military mental health partial hospitalization programs. In addition, this study offered data on the frequency of career-impacting medical recommendations made for patients engaged in care at this level of acuity.

Paradoxical relationships between active transport and global protein distributions in neurons.

Neural function depends on continual synthesis and targeted trafficking of intracellular components, including ion channel proteins. Many kinds of ion channels are trafficked over long distances to specific cellular compartments. This raises the question of whether cargo is directed with high specificity during transit or whether cargo is distributed widely and sequestered at specific sites. We addressed this question by experimentally measuring transport and expression densities of Kv4.2, a voltage-gated transient potassium channel that exhibits a specific dendritic expression that increases with distance from the soma and little or no functional expression in axons. In over 500 h of quantitative live imaging, we found substantially higher densities of actively transported Kv4.2 subunits in axons as opposed to dendrites. This paradoxical relationship between functional expression and traffic density supports a model-commonly known as the sushi belt model-in which trafficking specificity is relatively low and active sequestration occurs in compartments where cargo is expressed. In further support of this model, we find that kinetics of active transport differs qualitatively between axons and dendrites, with axons exhibiting strong superdiffusivity, whereas dendritic transport resembles a weakly directed random walk, promoting mixing and opportunity for sequestration. Finally, we use our data to constrain a compartmental reaction-diffusion model that can recapitulate the known Kv4.2 density profile. Together, our results show how nontrivial expression patterns can be maintained over long distances with a relatively simple trafficking mechanism and how the hallmarks of a global trafficking mechanism can be revealed in the kinetics and density of cargo.

Management of calcified coronary artery bifurcation lesions.

Calcified coronary artery bifurcation lesions (CBL) remain a challenge for the interventional cardiologist. Evidence regarding treatment of CBL is minimal. Optimal plaque modification is the most important step prior to stent deployment. Provisional stenting is the preferred strategy for most bifurcation lesions. However, two-stent strategy should be considered for BL with compromised large SB (>2.5 mm) supplying a large territory, >70% SB stenosis and lesions more than 5 mm long. In this contemporary review article, we present a simplified approach to treating CBL and demonstrate the approach to specific case examples using our newly developed mobile application, BifurcAID.

Cardiovascular outcomes after percutaneous coronary intervention on bifurcation lesions with moderate to severe coronary calcium: A single-center registry study.

BACKGROUND: Both target vessel calcification and target vessel bifurcation are associated with worse outcomes following percutaneous coronary intervention (PCI). Whether these entities in combination interact to influence outcomes after PCI of complex coronary disease is not known. OBJECTIVES: This study evaluated the association of target vessel bifurcation and target vessel calcification, alone and in combination, with adverse events following PCI. METHODS: Registry data from 21,165 patients who underwent PCI with drug-eluting stents (DES) between January 2009 and December 2017 were analyzed. Patients were divided into four groups according to the presence or absence of target vessel bifurcation and presence of none/mild or moderate/severe target vessel calcification on angiography. Associations between lesion groups and 1 year major adverse cardiac events (MACE) were examined using Cox regression analysis. RESULTS: At 1 year, unadjusted rates of MACE, death, myocardial infarction (MI), as well as stent thrombosis were highest in the group with both bifurcation lesion and moderate/severe calcification. After adjusting for confounders such as age, renal disease, and smoking, hazard ratios for MACE were 1.14 (95%CI 0.99-1.33) for bifurcation with none/mild calcification, 1.21 (95%CI 1.06-1.38) for no bifurcation and moderate/severe calcification, and 1.37 (95%CI 1.14-1.64) for bifurcation and moderate severe calcification, compared to patients with no bifurcation and none/mild calcification. CONCLUSIONS: The presence of a bifurcating target vessel with moderate/severe calcification is associated with a higher risk of adverse outcomes than either attribute alone. New approaches are needed to improve outcomes in this subset of patients with complex coronary artery disease.

Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltage-gated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies.SIGNIFICANCE STATEMENT Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures. FXS is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein, and the neuronal hyperexcitability observed in the absence of FMRP likely results from its ability to regulate the expression and activity of voltage-gated ion channels. Here we find that FMRP serves as a key translational regulator of the voltage-gated calcium channel Cav2.3 under basal conditions and following activity. Cav2.3 impacts cellular excitability and calcium signaling, and the alterations in channel translation and expression observed in the absence of FMRP could contribute to the neuronal hyperactivity that underlies FXS.

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels.

The Kv4 family of A-type voltage-gated K+ channels regulates the excitability in hippocampal pyramidal neuron dendrites and are key determinants of dendritic integration, spike timing-dependent plasticity, long-term potentiation, and learning. Kv4.2 channel expression is down-regulated following hippocampal seizures and in epilepsy, suggesting A-type currents as therapeutic targets. In addition to pore-forming Kv4 subunits, modulatory auxiliary subunits called K+ channel-interacting proteins (KChIPs) modulate Kv4 expression and activity and are required to recapitulate native hippocampal A-type currents in heterologous expression systems. KChIP mRNAs contain multiple start sites and alternative exons that generate considerable N-terminal variation and functional diversity in shaping Kv4 currents. As members of the EF-hand domain-containing neuronal Ca2+ sensor protein family, KChIP auxiliary proteins may convey Ca2+ sensitivity upon Kv4 channels; however, to what degree intracellular Ca2+ regulates KChIP-Kv4.2 complexes is unclear. To answer this question, we expressed KChIP2 with Kv4.2 in HEK293T cells, and, with whole-cell patch-clamp electrophysiology, measured an ∼1.5-fold increase in Kv4.2 current density in the presence of elevated intracellular Ca2+ Intriguingly, the Ca2+ regulation of Kv4 current was specific to KChIP2b and KChIP2c splice isoforms that lack a putative polybasic domain that is present in longer KChIP2a1 and KChIP2a isoforms. Site-directed acidification of the basic residues within the polybasic motif of KChIP2a1 rescued Ca2+-mediated regulation of Kv4 current density. These results support divergent Ca2+ regulation of Kv4 channels mediated by alternative splicing of KChIP2 isoforms. They suggest that distinct KChIP-Kv4 interactions may differentially control excitability and function of hippocampal dendrites.

A novel bungarotoxin binding site-tagged construct reveals MAPK-dependent Kv4.2 trafficking.

Kv4.2 voltage-gated K+ channel subunits, the primary source of the somatodendritic A-type K+ current in CA1 pyramidal neurons of the hippocampus, play important roles in regulating dendritic excitability and plasticity. To better study the trafficking and subcellular distribution of Kv4.2, we created and characterized a novel Kv4.2 construct encoding a bungarotoxin binding site in the extracellular S3-S4 linker region of the α-subunit. When expressed, this construct can be visualized in living cells after staining with rhodamine-conjugated bungarotoxin. We validated the utility of this construct by visualizing the spontaneous internalization and insertion of Kv4.2 in HEK 293T cells. We further report that Kv4.2 colocalized with several endosome markers in HEK 293T cells. In addition, Kv4.2 internalization is significantly impaired by mitogen-activated protein kinase (MAPK) inhibitors in transfected primary hippocampal neurons. Therefore, this newly developed BBS-Kv4.2 construct provides a novel and powerful tool for studying surface Kv4.2 channel localization and trafficking.

Monitoring processes in extended emotion regulation.

The extended process model of emotion regulation (ER) posits that dynamic ER processes monitor and adjust the implementation of ER strategies over time. When an initial ER strategy is ineffective, monitoring processes allow one to flexibly switch to a new, possibly more effective strategy. The present study employed a novel experimental task to explore these dynamic ER processes. Sixty-eight adult female participants each completed 40 trials. In each trial, participants first were assigned to use either distraction or reappraisal for the either low- or high-intensity negative image presented. Then, they were presented with a choice between continuing to use the assigned strategy or switching strategies before viewing the negative image again. Results showed that the combinations of ER strategies and image intensities generated different affect states for the choice context. The magnitude of intermediate negative affect was positively associated with a greater probability of choosing to switch strategies. Finally, for higher intermediate negative affect, negative affect was lower after choosing to switch strategies. For lower intermediate negative affect, negative affect remained low regardless of continuing or switching strategies. These findings support the extended process model and contribute to a growing body of empirical support for dynamic models of ER.

Thera-prov: a pilot study of improv used to treat anxiety and depression.

Background: Improvisational theater exercises (improv) are used in various settings to improve mental health and medical outcomes. However, there is little documented evidence of the effectiveness of these interventions.Aims: We developed a short-term, group intervention that used improv exercises in a therapeutic manner to treat psychiatric patients.Methods: We evaluated the feasibility, acceptability and five clinical outcomes (depressive symptoms, anxious symptoms, self-esteem, perfectionism and satisfaction with social roles) of this intervention in an outpatient setting. Participants were 32 patients with symptoms of anxiety and depression and who had variable exposure to psychiatric treatment.Results: In paired samples t-tests, participants demonstrated reduced symptoms of anxiety (t(31) = 4.67, p < 0.001) and depression (t(31) = 3.78, p = 0.001), and improved self-esteem (t(31)= -3.31, p = 0.002) following the intervention. There was a trend towards reduction of perfectionism (t(31) = 1.77, p = 0.087), but no substantial change in rated satisfaction with social roles. Effect sizes were medium for reduction in symptoms of depression and anxiety.Conclusions: The results of this study indicate that a brief intervention based on improv exercises may provide a strong and efficient treatment for patients with anxiety and depression.

Dynamic processes in emotion regulation choice.

Because emotion regulation (ER) processes operate over time, they potentially change the context in which subsequent ER processes occur. To test this proposal, fifty-two healthy participants completed the ER choice task. Thirty standardized low- and high-intensity negative images were used to generate different emotional contexts in which participants selected between distraction or reappraisal strategies to decrease the intensity of their negative emotion. Participants then implemented their selected strategy and rated their negative emotion. Using a dynamic perspective, we examined as predictors of ER strategy choice, in addition to current stimulus intensity, several contextual factors from the immediately preceding trial: preceding stimulus intensity and strategy choice, and the intensity of negative affect following the previous strategy implementation and thus preceding the current trial. Results replicated earlier findings that participants are more likely to choose distraction for high-intensity images. Extending earlier findings, selecting reappraisal in the preceding trial and greater negative affect preceding the current trial were associated with lower odds of choosing distraction. The lack of significant interactions among the current and preceding trial factors suggests that these effects on ER choice were direct and not through moderating the effect of current stimulus intensity. These findings support dynamic theories of ER.

Structure-based prediction of transcription factor binding specificity using an integrative energy function.

UNLABELLED: Transcription factors (TFs) regulate gene expression through binding to specific target DNA sites. Accurate annotation of transcription factor binding sites (TFBSs) at genome scale represents an essential step toward our understanding of gene regulation networks. In this article, we present a structure-based method for computational prediction of TFBSs using a novel, integrative energy (IE) function. The new energy function combines a multibody (MB) knowledge-based potential and two atomic energy terms (hydrogen bond and π interaction) that might not be accurately captured by the knowledge-based potential owing to the mean force nature and low count problem. We applied the new energy function to the TFBS prediction using a non-redundant dataset that consists of TFs from 12 different families. Our results show that the new IE function improves the prediction accuracy over the knowledge-based, statistical potentials, especially for homeodomain TFs, the second largest TF family in mammals. CONTACT: jguo4@uncc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Melanocortin-3 receptor regulates the normal fasting response.

The melanocortin-3 receptor-deficient (MC3-R(-/-)) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R(-/-) mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R(-/-) mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model.

Phenomenology of the sound-induced flash illusion.

Past studies, using pairings of auditory tones and visual flashes, which were static and coincident in space but variable in time, demonstrated errors in judging the temporal patterning of the visual flashes-the sound-induced flash illusion. These errors took one of the two forms: under-reporting (sound-induced fusion) or over-reporting (sound-induced fission) of the flash numbers. Our study had three objectives: to examine the robustness of both illusions and to consider the effects of stimulus set and response bias. To this end, we used an extended range of fixed spatial location flash-tone pairings, examined stimuli that were variable in space and time and measured confidence in judging flash numbers. Our results indicated that the sound-induced flash illusion is a robust percept, a finding underpinned by the confidence measures. Sound-induced fusion was found to be more robust than sound-induced fission and a most likely outcome when high numbers of flashes were incorporated within an incongruent flash-tone pairing. Conversely, sound-induced fission was the most likely outcome for the flash-tone pairing which contained two flashes. Fission was also shown to be strongly driven by stimuli confounds such as categorical boundary conditions (e.g. flash-tone pairings with ≤2 flashes) and compressed response options. These findings suggest whilst both fission and fusion are associated with 'auditory driving', the differences in the occurrence and strength of the two illusions not only reflect the separate neuronal mechanisms underlying audio and visual signal processing, but also the test conditions that have been used to investigate the sound-induced flash illusion.

Changes in emotion regulation difficulties and PTSD symptom severity in an intensive treatment program for PTSD.

BACKGROUND: Greater difficulties in emotion regulation (ER) and decreased use of adaptive ER strategies have been associated with higher levels of posttraumatic stress disorder (PTSD) symptoms. To date, limited research has explored whether ER improves with PTSD treatment or whether such improvements are linked with improvements in PTSD symptoms. METHODS: Veterans and service members with PTSD (N = 223) participated in a 2-week intensive treatment program (ITP) based in Cognitive Processing Therapy (CPT). ER was measured using the Difficulties in Emotion Regulation Short Form (DERS-SF) at baseline and on days 4 and 9 of treatment. PTSD symptoms were reported on the PTSD Symptom Checklist for DSM-5 (PCL-5) at baseline, on days 3, 5, 6, and 8 of treatment, and at post-treatment. RESULTS: DERS-SF scores decreased during treatment (Mchange = 5.12, d = 0.38). Baseline DERS-SF did not predict overall PCL-5 scores across timepoints (p = .377). However, scores on the DERS-SF over time were significantly associated with PCL-5 improvement over the course of treatment (p < .001, R2b = 0.07). Finally, improvements in all subscales of the DERS-SF across time except clarity were significantly associated with improvement in PCL-5 over time. LIMITATIONS: Additional treatment components in the ITP beyond CPT may have contributed to ER improvements. Conclusions are also limited by the use of self-report data. CONCLUSIONS: An intensive CPT-based treatment program for veterans and service members can lead to improved ER in two weeks. ER improvements are associated with PTSD symptom severity during the ITP.

Clinical Outcomes After Percutaneous Coronary Intervention for Left Main Coronary Artery Disease in Patients of Diverse Race/Ethnicity.

Data on percutaneous coronary intervention (PCI) for left main coronary artery (LMCA) disease in patients of diverse race/ethnicity is scant. The aim of the study was to assess the impact of race/ethnicity on clinical outcomes at 12-month follow-up of patients with LMCA disease undergoing PCI with drug-eluting stent implantation. All patients undergoing PCI for LMCA disease between 2010 and 2019 at a tertiary care center were prospectively enrolled. Clinical outcomes were assessed per each race/ethnic group. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months. A total of 774 consecutive patients with known race/ethnicity were prospectively enrolled, 62.1% (n=481) Caucasians, 17.2% (n=133) Hispanics, 12.7% (n=98) Asians and 8.0% (n=62) African Americans. Compared with Caucasians, the hazard rate of the primary endpoint tended to be lower in Asian patients (6.1% vs 14.2%; hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.16-1.03), and similar in African American (13.7% vs 14.2%; HR: 0.93; 95% CI: 0.40-2.16) and Hispanic patients (14.2% vs 14.2%; HR: 1.02; 95% CI: 0.58-1.78). Hazard rates of target vessel or lesion revascularization were comparable in the four groups. Cox multivariable regression adjustment confirmed consistent findings and revealed higher hazard rate of post-discharge bleeding in African Americans vs. Caucasians (HR: 5.89; 95% CI: 1.00-34.5). In conclusion, within a racially/ethnically diverse cohort of patients undergoing PCI for LMCA disease, when compared with Caucasians, Asians are at lower risk of all-cause death, MI or stroke, while African Americans are at increased risk of post-discharge bleeding.

Impact of Polyvascular Disease in Patients Undergoing Unprotected Left Main Percutaneous Coronary Intervention.

Percutaneous coronary intervention (PCI) has demonstrated its safety and efficacy in treating left main (LM) coronary artery disease (CAD) in select patients. Polyvascular disease (PolyVD) is associated with adverse events in all-comers with CAD. However, there is little data examining the interplay between PolyVD and LM-PCI, which we sought to investigate in a retrospective single-center study. We included patients who underwent unprotected LM-PCI at a tertiary center from 2012 to 2019. The study population was stratified based on the presence or absence of PolyVD (i.e., medical history of cerebrovascular and/or peripheral artery disease in addition to LM-CAD). The primary outcome was major adverse cardiovascular events (MACE) combining all-cause mortality and spontaneous myocardial infarction within 1 year after index PCI. Overall, 869 patients were included, and 23.8% of the population had PolyVD. Subjects with PolyVD were older and had a greater burden of co-morbidities. After 1-year follow-up, PolyVD patients exhibited significantly higher rates of both MACE (22.8% vs 9.4%, p <0.001) and bleeding events compared with those without PolyVD. MACE was primarily driven by an increase in all-cause mortality (18.3% vs 7.1%, p <0.001). Results persisted after adjusting for confounders. In conclusion, in patients who underwent LM-PCI, the presence of PolyVD is linked to an increased risk of MACE and bleeding after 1 year of follow-up, which highlights the vulnerability of this population.

Surface electromyographic frequency characteristics of the quadriceps differ between continuous high- and low-torque isometric knee extension to momentary failure.

Surface EMG (sEMG) has been used to compare loading conditions during exercise. Studies often explore mean/median frequencies. This potentially misses more nuanced electrophysiological differences between exercise tasks. Therefore, wavelet-based analysis was used to evaluate electrophysiological characteristics in the sEMG signal of the quadriceps under both higher- and lower-torque (70 % and 30 % of MVC, respectively) isometric knee extension performed to momentary failure. Ten recreationally active adult males with previous resistance training experience were recruited. Using a within-session, repeated-measures, randomised crossover design, participants performed isometric knee extension whilst sEMG was collected from the vastus medialis (VM), rectus femoris (RF) and vastus lateralis (VL). Mean signal frequency showed similar characteristics in each condition at momentary failure. However, individual wavelets revealed different frequency component changes between the conditions. All frequency components increased during the low-torque condition. But low-frequency components increased, and high-frequency components decreased, in intensity throughout the high-torque condition. This resulted in convergence of the low-torque and high-torque trial wavelet characteristics towards the end of the low-torque trial. Our results demonstrate a convergence of myoelectric signal properties between low- and high-torque efforts with fatigue via divergent signal adaptations. Further work should disentangle factors influencing frequency characteristics during exercise tasks.

Transport between im/mobile fractions shapes the speed and profile of cargo distribution in neurons.

Neuronal function requires continuous distribution of ion channels and other proteins throughout large cell morphologies. Protein distribution is complicated by immobilization of freely diffusing subunits such as on lipid rafts or in postsynaptic densities. Here, we infer rates of immobilization for the voltage-gated potassium channel Kv4.2. Fluorescence recovery after photobleaching quantifies protein diffusion kinetics, typically reported as a recovery rate and mobile fraction. We show that, implicit in the fluorescence recovery, are rates of particle transfer between mobile and immobile fractions (im/mobilization). We performed photobleaching of fluorescein-tagged ion channel Kv4.2-sGFP2 in over 450 dendrites of rat hippocampal cells. Using mass-action models, we infer rates of Kv4.2-sGFP2 im/mobilization. Using a realistic neuron morphology, we show how these rates shape the speed and profile of subunit distribution. The experimental protocol and model inference introduced here is widely applicable to other cargo and experimental systems.

R-type voltage-gated Ca2+ channels mediate A-type K+ current regulation of synaptic input in hippocampal dendrites.

The subthreshold voltage-gated transient K+ current (IA) carried by pore-forming Kv4.2 subunits regulates the propagation of synaptic input, dendritic excitability, and synaptic plasticity in CA1 pyramidal neuron dendrites of the hippocampus. We report that the Ca2+ channel subunit Cav2.3 regulates IA in this cell type. We initially identified Cav2.3 as a Kv4.2-interacting protein in a proteomic screen and we confirmed Cav2.3-Kv4.2 complex association using multiple techniques. Functionally, Cav2.3 Ca2+-entry increases Kv4.2-mediated whole-cell current due to an increase in Kv4.2 surface expression. Using pharmacology and Cav2.3 knockout mice, we show that Cav2.3 regulates the dendritic gradient of IA. Furthermore, the loss of Cav2.3 function leads to the enhancement of AMPA receptor-mediated synaptic currents and NMDA receptor-mediated spine Ca2+ influx. These results propose that Cav2.3 and Kv4.2 are integral constituents of an ion channel complex that affects synaptic function in the hippocampus.