CaV3.1 T-type calcium channels are important for spatial memory processing in the dorsal subiculum.

The dorsal subiculum (dSub) is one of the key structures responsible for the formation of hippocampal memory traces but the contribution of individual ionic currents to its cognitive function is not well studied. Although we recently reported that low-voltage-activated T-type calcium channels (T-channels) are crucial for the burst firing pattern regulation in the dSub pyramidal neurons, their potential role in learning and memory remains unclear. Here we used in vivo local field potential recordings and miniscope calcium imaging in freely behaving mice coupled with pharmacological and genetic tools to address this gap in knowledge. We show that the CaV3.1 isoform of T-channels is critically involved in controlling neuronal activity in the dSub in vivo. Altering neuronal excitability by inhibiting T-channel activity markedly affects calcium dynamics, synaptic plasticity, neuronal oscillations and phase-amplitude coupling in the dSub, thereby disrupting spatial learning. These results provide an important causative link between the CaV3.1 channels, burst firing of dSub neurons and memory formation, thus further supporting the notion that changes in neuronal excitability regulate memory processing. We posit that subicular CaV3.1 T-channels could be a promising novel drug target for cognitive disorders.

Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.

Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.

The Effects of Social, Personal, and Behavioral Risk Factors and PM2.5 on Cardio-Metabolic Disparities in a Cohort of Community Health Center Patients.

(1) Background: Cardio-metabolic diseases (CMD), including cardiovascular disease, stroke, and diabetes, have numerous common individual and environmental risk factors. Yet, few studies to date have considered how these multiple risk factors together affect CMD disparities between Blacks and Whites. (2) Methods: We linked daily fine particulate matter (PM2.5) measures with survey responses of participants in the Southern Community Cohort Study (SCCS). Generalized linear mixed modeling (GLMM) was used to estimate the relationship between CMD risk and social-demographic characteristics, behavioral and personal risk factors, and exposure levels of PM2.5. (3) Results: The study resulted in four key findings: (1) PM2.5 concentration level was significantly associated with reported CMD, with risk rising by 2.6% for each µg/m3 increase in PM2.5; (2) race did not predict CMD risk when clinical, lifestyle, and environmental risk factors were accounted for; (3) a significant variation of CMD risk was found among participants across states; and (4) multiple personal, clinical, and social-demographic and environmental risk factors played a role in predicting CMD occurrence. (4) Conclusions: Disparities in CMD risk among low social status populations reflect the complex interactions of exposures and cumulative risks for CMD contributed by different personal and environmental factors from natural, built, and social environments.

Alterations in Oscillatory Behavior of Central Medial Thalamic Neurons Demonstrate a Key Role of CaV3.1 Isoform of T-Channels During Isoflurane-Induced Anesthesia.

Although the central medial nucleus (CeM) of the thalamus is an essential part of the arousal system for sleep and anesthesia initiation, the precise mechanisms that regulate its activity are not well studied. We examined the role of CaV3.1 isoform of T-type calcium channels (T-channels) in the excitability and rhythmic activity of CeM neurons during isoflurane (ISO)-induced anesthesia by using mouse genetics and selective pharmacology. Patch-clamp recordings taken from acute brain slices revealed that CaV3.1 channels in CeM are inhibited by prototypical volatile anesthetic ISO (250 and 500 µM) and selective T-channels blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). Both TTA-P2 and ISO attenuated tonic and burst firing modes, and hyperpolarized CeM neurons from wild type (WT) mice. These effects were greatly diminished or abolished in CaV3.1 null mice. Our ensuing in vivo local field potential (LFP) recordings from CeM indicated that the ability of TTA-P2 and anesthetic concentrations of ISO to promote δ oscillation was substantially weakened in CaV3.1 null mice. Furthermore, escalating ISO concentrations induced stronger burst-suppression LFP pattern in mutant than in WT mice. Our results demonstrate for the first time the importance of CaV3.1 channels in thalamocortical oscillations from the non-specific thalamic nuclei that underlie clinically important effects of ISO.

Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic-ischemic encephalopathy.

Research studies suggest that neonatal seizures, which are most commonly associated with hypoxic-ischemic injury, may contribute to brain injury and adverse neurologic outcome. Unfortunately, neonatal seizures are often resistant to treatment with current anticonvulsants. In the present study, we evaluated the efficacy of flupirtine, administered at clinically relevant time-points, for the treatment of neonatal seizures in an animal model of hypoxic-ischemic injury that closely replicates features of the human syndrome. We also compared the efficacy of flupirtine to that of phenobarbital, the current first-line drug for neonatal seizures. Flupirtine is a KCNQ potassium channel opener. KCNQ channels play an important role in controlling brain excitability during early development. In this study, hypoxic-ischemic injury was induced in neonatal rats, and synchronized video-EEG records were acquired at various time-points during the experiment to identify seizures. The results revealed that flupirtine, administered either 5 min after the first electroclinical seizure, or following completion of 2 h of hypoxia, i.e., during the immediate reperfusion period, reduced the number of rats with electroclinical seizures, and also the frequency and total duration of electroclinical seizures. Further, daily dosing of flupirtine decreased the seizure burden over 3 days following HI-induction, and modified the natural evolution of acute seizures. Moreover, compared to a therapeutic dose of phenobarbital, which was modestly effective against electroclinical seizures, flupirtine showed greater efficacy. Our results indicate that flupirtine is an extremely effective treatment for neonatal seizures in rats and provide evidence for a trial of this medication in newborn humans.

Local variation in public health preparedness: lessons from California.

Since September 2001 Congress has allocated approximately dollars 3 billion to strengthen the public health infrastructure. To achieve this goal, the U.S. Centers for Disease Control and Prevention (CDC) allocates funding to states, which distribute funds to local jurisdictions. Evidence-based measures to assess public health preparedness are lacking. We used an expert-panel process to develop performance measures, based on the ten essential public health services. We developed and conducted tabletop exercises in California to evaluate preparedness to detect and respond to a hypothetical smallpox outbreak based on those measures. There was wide variation of readiness in California. While the sources of variation are often different, common infrastructure gaps need to be addressed.

Socioeconomic, cultural, and behavioral factors affecting Hispanic health outcomes.

Evidence suggests that social and economic factors are important determinants of health. Yet, despite higher porverty rates, less education, and worse access to health care, health outcomes of many Hispanics living in the United States today are equal to, or better than, those of non-Hispanic whites. This paradox is described in the literature as the epidemiological paradox or Hispanic health paradox. In this paper, the authors selectively review data and research supporting the existence of the epidemiological paradox. They find substantial support for the existence of the epidemiological paradox, particularly among Mexican Americans. Census undercounts of Hispanics, misclassification of Hispanic deaths, and emigration of Hispanics do not fully account for the epidemiological paradox. Identifying protective factors underlying the epidemiological paradox, while improving access to care and the economic conditions among Hispanics, are important research and policy implications of this review.