Long-term potentiation in neurogliaform interneurons modulates excitation-inhibition balance in the temporoammonic pathway

Apical dendrites of pyramidal neurons integrate information from higher-order cortex and thalamus, and gate signalling and plasticity at proximal synapses. In the hippocampus, neurogliaform cells and other interneurons located within stratum lacunosum-moleculare mediate powerful inhibition of CA1 pyramidal neuron distal dendrites. Is the recruitment of such inhibition itself subject to use-dependent plasticity, and if so, what induction rules apply? Here we show that interneurons in mouse stratum lacunosum-moleculare exhibit Hebbian NMDA receptor-dependent long-term potentiation (LTP). Such plasticity can be induced by selective optogenetic stimulation of afferents in the temporoammonic pathway from the entorhinal cortex, but not by equivalent stimulation of afferents from the thalamic nucleus reuniens. We further show that theta-burst patterns of afferent firing induces LTP in neurogliaform interneurons identified using neuron-derived neurotrophic factor (Ndnf)-Cre mice. Theta-burst activity of entorhinal cortex afferents led to an increase in disynaptic feed-forward inhibition, but not monosynaptic excitation, of CA1 pyramidal neurons. Activity-dependent synaptic plasticity in stratum lacunosum-moleculare interneurons thus alters the excitation-inhibition balance at entorhinal cortex inputs to the apical dendrites of pyramidal neurons, implying a dynamic role for these interneurons in gating CA1 dendritic computations. Abstract figure legend Hebbian LTP of excitatory transmission onto interneurons located within hippocampal stratum lacunosum moleculare (SLM) can be induced by electrical stimulation protocols involving pairing of pre-and post-synaptic activity. Using Ndnf-Cre mice, we show that hippocampal neurogliaform (NGF) cells express this form of LTP. These cells receive glutamatergic afferents from both the nucleus reuniens of the thalamus and the entorhinal cortex (EC), but selective optogenetic activation of either set of fibers reveals LTP at EC inputs only. Using an optogenetic theta-burst stimulation (OptoTBS) protocol to stimulate EC fibers in a physiologically relevant way, we show that NGF interneuron LTP translates to an increase in disynaptic inhibition onto CA1 pyramidal cell distal dendrites. Monosynaptic EC-CA1 pyramidal cell inputs do not undergo equivalent potentiation, leading to a net decrease in the excitation/inhibition (E/I) ratio of this pathway

Strong Association of a Common Dihydropyrimidine Dehydrogenase Gene Polymorphism with Fluoropyrimidine-Related Toxicity in Cancer Patients

variations associated with enhanced drug toxicity. = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies. polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

One million cubic kilometers of fossil ice in Valles Marineris: Relicts of a 3.5 Gy old glacial landsystem along the Martian equator

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