Altered hippocampal interneuron activity precedes ictal onset.

Although failure of GABAergic inhibition is a commonly hypothesized mechanism underlying seizure disorders, the series of events that precipitate a rapid shift from healthy to ictal activity remain unclear. Furthermore, the diversity of inhibitory interneuron populations poses a challenge for understanding local circuit interactions during seizure initiation. Using a combined optogenetic and electrophysiological approach, we examined the activity of identified mouse hippocampal interneuron classes during chemoconvulsant seizure induction in vivo. Surprisingly, synaptic inhibition from parvalbumin- (PV) and somatostatin-expressing (SST) interneurons remained intact throughout the preictal period and early ictal phase. However, these two sources of inhibition exhibited cell-type-specific differences in their preictal firing patterns and sensitivity to input. Our findings suggest that the onset of ictal activity is not associated with loss of firing by these interneurons or a failure of synaptic inhibition but is instead linked with disruptions of the respective roles these interneurons play in the hippocampal circuit.

Noninvasive optical inhibition with a red-shifted microbial rhodopsin.

Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red light-induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience.

Urinary lipoarabinomannan as predictor for the tuberculosis immune reconstitution inflammatory syndrome.

BACKGROUND: Upon initiation of antiretroviral therapy (ART), 15.7% [95% confidence interval (CI): 9.7% to 24.5%] of tuberculosis (TB)-HIV-coinfected individuals experience paradoxical worsening of their clinical status with exuberant inflammation consistent with immune reconstitution inflammatory syndrome (IRIS). We investigated whether a positive urinary TB lipoarabinomannan (LAM) antigen enzyme-linked immunosorbent assay test before ART initiation was associated with development of paradoxical TB-IRIS. METHODS: In a prospective observational cohort in Mulago Hospital, Kampala, Uganda, we measured pre-ART urinary LAM concentrations in HIV-infected patients on TB treatment. Patients who developed TB-IRIS (according to the International Network for the Study of HIV-associated IRIS case definition) were compared with patients who remained IRIS free for at least 3 months. RESULTS: Twenty-six individuals with TB-IRIS and 64 without IRIS were included in the analysis. The median time to TB-IRIS was 14 days (interquartile range: 11-14 days). Univariate analysis showed that a positive pre-ART urinary LAM test [OR: 4.6 (95% CI: 1.5 to 13.8), P = 0.006] and a CD4 count <50 cells/mL [OR: 21 (95% CI: 2.6 to 169.4), P = 0.004] were associated with an increased risk of TB-IRIS. In multivariate analysis, only a baseline CD4 T-cell count <50 cells/mL was predictive of IRIS (P < 0.004). Sensitivity and specificity of a positive pre-ART urinary LAM test to diagnose IRIS were 80.8% (95% CI: 60.6 to 93.4) and 52.4% (95% CI: 39.4 to 65.1), respectively. CONCLUSIONS: If CD4 T-cell count testing is available, a pre-highly active antiretroviral therapy urinary LAM test has no added value to predict TB-IRIS. When CD4 T-cell count is not available, a positive LAM test could identify patients at increased risk of TB-IRIS.

Association of the small GTPase Rheb with the NMDA receptor subunit NR3A.

The NMDAR subunit NR3A is most highly expressed during the second postnatal week, when synaptogenesis reaches peak levels. Genetic ablation or overexpression of the NR3A subunit negatively interferes with the maturation of cortical synapses and leads to changes in the shape and number of dendritic spines, the density of which is increased in NR3A knock-out mice and decreased in NR3A-overexpressing transgenic mice. Alterations in spine density have been linked to dysregulation of mTOR signaling and synaptic protein translation. Using a yeast two-hybrid system, we identified the mTOR-activating GTPase Rheb as an interacting protein of the NMDAR subunit NR3A. We confirmed the interaction in mammalian cells by expressing recombinant Rheb and NR3A and showed that Rheb and NR3A could be co-immunoprecipitated from synaptic plasma membranes from the developing rat brain. These data suggest that NR3A sequesters synaptic Rheb and might thus function as a break of the mTOR-dependent synaptic translation of protein.