The Sodium Current Underlying Action-Potentials in Guinea-Pig Hippocampal Ca1 Neurons

Neurons were acutely dissociated from the CA1 region of hippocampal slices from guinea pigs. Whole-cell recording techniques were used to record and control membrane potential. When the electrode contained KF, the average resting potential was about -40 mV and action potentials in cells at -80 mV (current-clamped) had an amplitude greater than 100 mV. Cells were voltage-clamped at 22-24 degrees C with electrodes containing CsF. Inward currents generated with depolarizing voltage pulses reversed close to the sodium equilibrium potential and could be completely blocked with tetrodotoxin (1 microM). The amplitude of these sodium currents was maximal at about -20 mV and the amplitude of the tail currents was linear with potential, which indicates that the channels were ohmic. The sodium conductance increased with depolarization in a range from -60 to 0 mV with an average half-maximum at about -40 mV. The decay of the currents was not exponential at potentials more positive than -20 mV. The time to peak and half-decay time of the currents varied with potential and temperature. Half of the channels were inactivated at a potential of -75 mV and inactivation was essentially complete at -40 to -30 mV. Recovery from inactivation was not exponential and the rate varied with potential. At lower temperatures, the amplitude of sodium currents decreased, their time course became longer, and half-maximal inactivation shifted to more negative potentials. In a small fraction of cells studied, sodium currents were much more rapid but the voltage dependence of activation and inactivation was very similar

Treatment of Young Children with HIV Infection: Using Evidence to Inform Policymakers

PMCID: PMC3404108This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Allosteric antagonist action at triheteromeric NMDA receptors

NMDA receptors are one subtype of glutamate receptor that play fundamental roles in synaptic physiology and synaptic plasticity in the nervous system, in addition to being implicated in several neurological disorders. It is now established that many NMDA receptors in the nervous system are triheteromeric, composed of two glycine-binding GluN1 subunits and two different glutamate binding GluN2 subunits. The pharmacology of NMDA receptor has become well established since the pioneering work of Watkins and Evans almost half a century ago and has seen a resurgence of interest in the past decade as new subtype-selective allosteric modulators have been discovered. In this article, features specific to allosteric antagonist action at triheteromeric NMDA receptors are reviewed with a focus on understanding the mechanism of action of drugs acting at triheteromeric GluN1/GluN2B/GluN2D receptors. These receptors are of importance in the basal ganglia and in interneurons of the hippocampus and implications for understanding the action of allosteric antagonists at synaptic triheteromeric receptors are considered

Choline and acetylcholine: what a difference an acetate makes

Choline is a water soluble B-group vitamin, which humans must consume through their diet to remain healthy. Meat, eggs and yeast extract are great sources of choline, an essential component of cell membranes and also the precursor of the neurotransmitter, acetylcholine (ACh)

Tuberculosis incidence is high in HIV-infected African children but is reduced by co-trimoxazole and time on antiretroviral therapy

BACKGROUND: There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis. METHODS: Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models. RESULTS: After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95 % CI, 1.5-2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2-13.4) versus 1.2/100 child-years (0.8-1.6) after 52 weeks). A higher TB risk was independently associated with younger age (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI + 2NRTI. Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue) = 3.0 (95 % CI, 1.1-8.3), P = 0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001). CONCLUSIONS: TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB

Early-stage [123I]beta-CIT SPECT and long-term clinical follow-up in patients with an initial diagnosis of Parkinson's disease

beta-CIT binding in both caudate nuclei was lower than in the group of patients with IPD. In addition, putamen to caudate binding ratios were higher in the group of APS patients. In spite of these differences, individual binding values showed considerable overlap between the groups. CONCLUSION: [(123)I]beta-CIT SPECT scanning in early-stage, untreated parkinsonian patients revealed a relative sparing of the caudate nucleus in patients with IPD as compared to patients later (re)diagnosed with APS. Nevertheless, the pattern of striatal involvement appears to have little predictive value for a later re-diagnosis of APS in individual case

Mg2+ block properties of triheteromeric GluN1-GluN2B-GluN2D NMDA receptors on neonatal rat substantia nigra pars compacta dopaminergic neurones

Native NMDA receptors (NMDARs) are tetrameric channels formed by two GluN1 and two GluN2 subunits. So far, seven NMDARs subunits have been identified and they can form diheteromeric or triheteromeric NMDARs (more than one type of GluN2 subunit). Extracellular Mg2+ is an important regulator of NMDARs, and particularly the voltage dependence of Mg2+ block is crucial to the roles of NMDARs in synaptic plasticity and the integration of synaptic activity with neuronal activity. Although the Mg2+ block properties of diheteromeric NMDARs are fully investigated, properties of triheteromeric NMDARs are still not clear. Our previous data suggested that dopaminergic neurones expressed triheteromeric GluN1–GluN2B–GluN2D NMDARs. Here, using NMDARs in dopaminergic neurones from postnatal day 7 (P7) rats as a model system, we characterize the voltage-dependent Mg2+ block properties of triheteromeric NMDARs. In control conditions, external Mg2+ significantly inhibits the whole cell NMDA-evoked current in a voltage-dependent manner with IC50 values of 20.9 μm, 53.3 μm and 173 μm at −90 mV, −70 mV and −50 mV, respectively. When the GluN2B-selective antagonist ifenprodil was applied, the Mg2+ sensitivity of the residual NMDA-mediated currents (which is mainly carried by GluN1–GluN2B–GluN2D NMDARs) is reduced to IC50 values of 45.9 μm (−90 mV), 104 μm (−70 mV) and 276 μm (−50 mV), suggesting that triheteromeric GluN1–GluN2B–GluN2D NMDARs have less affinity for external Mg2+ than GluN1–GluN2B receptors. In addition, fitting INMDA–V curves with a trapping Mg2+ block model shows the triheteromeric GluN1–GluN2B–GluN2D NMDARs have weaker voltage-dependent Mg2+ block (δ = 0.56) than GluN1–GluN2B NMDARs. Finally, our concentration jump and single channel recordings suggest that GluN1–GluN2B–GluN2D rather than GluN1–GluN2D NMDARs are present. These data provide information relevant to Mg2+ block characteristics of triheteromeric NMDARs and may help to better understand synaptic plasticity, which is dependent on these triheteromeric NMDARs

Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling

Synapse degeneration in the striatum has been associated with the early stages of Parkinson’s and Huntington’s diseases (PD and HD). However, the molecular mechanisms that trigger synaptic dysfunction and loss are not fully understood. Increasing evidence suggests that deficiency in Wnt signaling triggers synapse degeneration in the adult brain and that this pathway is affected in neurodegenerative diseases. Here, we demonstrate that endogenous Wnt signaling is essential for the integrity of a subset of inhibitory synapses on striatal medium spiny neurons (MSNs). We found that inducible expression of the specific Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum leads to the loss of inhibitory synapses on MSNs and affects the synaptic transmission of D2-MSNs. We also discovered that re-activation of the Wnt pathway by turning off Dkk1 expression after substantial loss of synapses resulted in the complete recovery of GABAergic and dopamine synapse number. Our results also show that re-activation of the Wnt pathway leads to a recovery of amphetamine response and motor function. Our studies identify the Wnt signaling pathway as a potential therapeutic target for restoring neuronal circuits after synapse degeneration

Growth and Neurodevelopment of HIV-Exposed Uninfected Children: a Conceptual Framework

PURPOSE OF THE REVIEW: The population of HIV-exposed uninfected (HEU) children is expanding rapidly, and over one million HEU infants are born each year globally. Several recent studies have reported that HEU children, particularly in low- and middle-income countries, are at risk of poor outcomes, including impaired growth and neurodevelopment. However, the reasons for poor clinical outcomes amongst HEU children remain unclear. RECENT FINDINGS: We summarise the findings from recent large studies that have characterised growth and neurodevelopment in HEU children, identified risk factors and explored underlying mechanistic pathways. We propose a conceptual framework to explain how exposure to HIV and antiretroviral therapy (ART) may lead to adverse growth and neurodevelopment in uninfected children, and review the available evidence and research gaps. SUMMARY: We propose that HEU children are affected both indirectly, through the augmentation of universal risk factors underlying poor growth and neurodevelopment, and directly through HIV/ART-specific pathways, which ultimately may converge through a series of common pathogenic mechanisms. In the era of universal ART, a better understanding of these pathways is crucial to inform future prevention and intervention strategies