Development of the translaminar circuits in the mouse cortex

The elaborated connections among cortical neurons form the cortical circuits, which are essential mechanisms underlying various cortical functions such as sensory perception, motor control, and other cognitive functions. The cortical circuits are composed of excitatory neurons and GABAergic interneurons. Excitatory neurons send excitatory connections to cortical neurons, while inhibitory neurons send inhibitory connections. Building the neural circuits is no easy task involving complex genetic programs and the influence of the environment through sensation. Malformation of the cortical circuits during development is implicated in causing neurological disorders, but our knowledge about the developmental process is scarce. The work in this dissertation uses in vitro electrophysiology in brain slices from transgenic mice to investigate how the excitatory connections onto GABAergic interneurons in the primary auditory cortex develop during the first two postnatal weeks. Furthermore, this dissertation explores the mechanisms that could regulate the early development of the cortical circuits by testing the requirement of sensory epithelium and N-methyl-D-aspartate receptors (NMDARs) in the early postnatal development of the neural circuits in the primary sensory cortex and temporal association cortex (TeA), respectively. Results from these studies fill crucial gaps in our understanding of how GABAergic interneurons are integrated into the cortical circuits and highlight the importance of sensory epithelium in the normal development of excitatory connections onto cortical GABAergic interneurons. My results also showed impaired development of GABAergic connections onto excitatory neurons lacking functional NMDARs in the TeA, suggesting an essential role of NMDARs for the early development of inhibitory circuits in the cortex

Development of cortical connections in the absence of NMDA receptors

slice recordings, LSPSFigure dataNIH RO1DC009607, NIH R01GM05648

Causal relationship between Alzheimer’s disease and prostate cancer: a bidirectional Mendelian randomization analysis

BackgroundPrevious observational researchers have found an inverse bidirectional link between Alzheimer’s disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted.MethodsThis study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran’s Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables.ConclusionThe results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD

Cortical inhibitory but not excitatory synaptic transmission and circuit refinement are altered after the deletion of NMDA receptors during early development

Abstract Neurons in the cerebral cortex form excitatory and inhibitory circuits with specific laminar locations. The mechanisms underlying the development of these spatially specific circuits is not fully understood. To test if postsynaptic N-methyl-D-aspartate (NMDA) receptors on excitatory neurons are required for the development of specific circuits to these neurons, we genetically ablated NMDA receptors from a subset of excitatory neurons in the temporal association cortex (TeA) through in utero electroporation and assessed the intracortical circuits connecting to L5 neurons through in vitro whole-cell patch clamp recordings coupled with laser-scanning photostimulation (LSPS). In NMDAR knockout neurons, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated connections were largely intact. In contrast both LSPS and mini-IPSC recordings revealed that γ-aminobutyric acid type A (GABAA) receptor-mediated connections were impaired in NMDAR knockout neurons. These results suggest that postsynaptic NMDA receptors are important for the development of GABAergic circuits

DataSheet_1_Causal relationship between Alzheimer’s disease and prostate cancer: a bidirectional Mendelian randomization analysis.docx

BackgroundPrevious observational researchers have found an inverse bidirectional link between Alzheimer’s disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted.MethodsThis study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran’s Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables.ConclusionThe results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.</p

Table_1_Causal relationship between Alzheimer’s disease and prostate cancer: a bidirectional Mendelian randomization analysis.xlsx

BackgroundPrevious observational researchers have found an inverse bidirectional link between Alzheimer’s disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted.MethodsThis study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran’s Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables.ConclusionThe results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.</p

DataSheet_1_Potential causal association between aspirin use and erectile dysfunction in European population: a Mendelian randomization study.docx

BackgroundAspirin, as one of the most commonly used drugs, possesses a broad spectrum of therapeutic applications. Presently, the potential association between aspirin usage and the risk elevation of erectile dysfunction (ED) remains inconclusive. The objective of this study employing two-sample Mendelian randomization (MR) was to clarify the causal impact of aspirin use on the risk of ED.MethodsThis study incorporated two sets of Genome-Wide Association Study (GWAS) summary statistics, one for aspirin use (46,946 cases and 286,635 controls) and another for ED (6,175 cases and 217,630 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate the causal effect of aspirin usage on the risk of ED development. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran’s Q test was adopted to check heterogeneity, and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association between genetically inferred aspirin use and ED was found by using inverse variance weighted (OR = 20.896, 95% confidence interval = 2.077-2.102E+2, P = 0.010). The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. Furthermore, the leave-one-out analysis demonstrated that the findings were not significantly affected by any instrumental variables.ConclusionThe results of this study highlighted the significance of aspirin use as a predisposing factor for ED and provided further evidence supporting the causal association between aspirin utilization and ED within European populations.</p

Image_1_Causal relationship between Alzheimer’s disease and prostate cancer: a bidirectional Mendelian randomization analysis.pdf

BackgroundPrevious observational researchers have found an inverse bidirectional link between Alzheimer’s disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted.MethodsThis study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran’s Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results.ResultsThe causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables.ConclusionThe results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.</p

Developmental and Activity-Dependent Expression of LanCL1 Confers Antioxidant Activity Required for Neuronal Survival

SummaryProduction of reactive oxygen species (ROS) increases with neuronal activity that accompanies synaptic development and function. Transcription-related factors and metabolic enzymes that are expressed in all tissues have been described to counteract neuronal ROS to prevent oxidative damage. Here, we describe the antioxidant gene LanCL1 that is prominently enriched in brain neurons. Its expression is developmentally regulated and induced by neuronal activity, neurotrophic factors implicated in neuronal plasticity and survival, and oxidative stress. Genetic deletion of LanCL1 causes enhanced accumulation of ROS in brain, as well as development-related lipid, protein, and DNA damage; mitochondrial dysfunction; and apoptotic neurodegeneration. LanCL1 transgene protects neurons from ROS. LanCL1 protein purified from eukaryotic cells catalyzes the formation of thioether products similar to glutathione S-transferase. These studies reveal a neuron-specific glutathione defense mechanism that is essential for neuronal function and survival