Distinct properties of layer 3 pyramidal neurons from prefrontal and parietal areas of the monkey neocortex

In primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch-clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (RS-L3PNs) and bursting (B-L3PNs) physiological subtypes. Whereas regional differences in single-cell excitability were modest, B-L3PNs were rare in PPC (RS-L3PN:BL3PN, 94:6), but were abundant in DLPFC (50:50), showing greater physiological diversity. Moreover, DLPFC L3PNs display larger and more complex basal dendrites with higher dendritic spine density. Additionally, we found differential expression of hundreds of genes, suggesting a transcriptional basis for the differences in L3PN phenotype between DLPFC and PPC. These data show that the previously observed differences between DLPFC and PPC neuron activity during working memory tasks are associated with diversity in the cellular/ molecular properties of L3PNs.Fil: Gonzalez Burgos, Guillermo. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Miyamae, Takeaki. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Krimer, Yosef. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Gulchina, Yelena. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Krimer, Olga. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Bazmi, Holly. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Arion, Dominique. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Enwright, John F.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Fish, Kenneth N.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Lewis, David A.. Univeristy of Pittsburgh. School of Medicine; Estados Unido

ICF, An Immunodeficiency Syndrome: DNA Methyltransferase 3B Involvement, Chromosome Anomalies, and Gene Dysregulation

The immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) is the only disease known to result from a mutated DNA methyltransferase gene, namely, DNMT3B. Characteristic of this recessive disease are decreases in serum immunoglobulins despite the presence of B cells and, in the juxtacentromeric heterochromatin of chromosomes 1 and 16, chromatin decondensation, distinctive rearrangements, and satellite DNA hypomethylation. Although DNMT3B is involved in specific associations with histone deacetylases, HP1, other DNMTs, chromatin remodelling proteins, condensin, and other nuclear proteins, it is probably the partial loss of catalytic activity that is responsible for the disease. In microarray experiments and real-time RT-PCR assays, we observed significant differences in RNA levels from ICF vs. control lymphoblasts for pro- and anti-apoptotic genes (BCL2L10, CASP1, and PTPN13); nitrous oxide, carbon monoxide, NF-κB, and TNFa signalling pathway genes (PRKCH, GUCY1A3, GUCY1B3, MAPK13; HMOX1, and MAP4K4); and transcription control genes (NR2F2 and SMARCA2). This gene dysregulation could contribute to the immunodeficiency and other symptoms of ICF and might result from the limited losses of DNA methylation although ICF-related promoter hypomethylation was not observed for six of the above examined genes. We propose that hypomethylation of satellite 2at1qh and 16qh might provoke this dysregulation gene expression by trans effects from altered sequestration of transcription factors, changes in nuclear architecture, or expression of noncoding RNAs

Comparative Pathway Integrator: A Framework of Meta-Analytic Integration of Multiple Transcriptomic Studies for Consensual and Differential Pathway Analysis

Pathway enrichment analysis provides a knowledge-driven approach to interpret differentially expressed genes associated with disease status. Many tools have been developed to analyze a single study. However, when multiple studies of different conditions are jointly analyzed, novel integrative tools are needed. In addition, pathway redundancy introduced by combining multiple public pathway databases hinders interpretation and knowledge discovery. We present a meta-analytic integration tool, Comparative Pathway Integrator (CPI), to address these issues using adaptively weighted Fisher’s method to discover consensual and differential enrichment patterns, a tight clustering algorithm to reduce pathway redundancy, and a text mining algorithm to assist interpretation of the pathway clusters. We applied CPI to jointly analyze six psychiatric disorder transcriptomic studies to demonstrate its effectiveness, and found functions confirmed by previous biological studies as well as novel enrichment patterns. CPI’s R package is accessible online on Github metaOmics/MetaPath

GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons.

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia

Assessing coastal wetland vulnerability to sea-level rise along the northern Gulf of Mexico coast: Gaps and opportunities for developing a coordinated regional sampling network.

Coastal wetland responses to sea-level rise are greatly influenced by biogeomorphic processes that affect wetland surface elevation. Small changes in elevation relative to sea level can lead to comparatively large changes in ecosystem structure, function, and stability. The surface elevation table-marker horizon (SET-MH) approach is being used globally to quantify the relative contributions of processes affecting wetland elevation change. Historically, SET-MH measurements have been obtained at local scales to address site-specific research questions. However, in the face of accelerated sea-level rise, there is an increasing need for elevation change network data that can be incorporated into regional ecological models and vulnerability assessments. In particular, there is a need for long-term, high-temporal resolution data that are strategically distributed across ecologically-relevant abiotic gradients. Here, we quantify the distribution of SET-MH stations along the northern Gulf of Mexico coast (USA) across political boundaries (states), wetland habitats, and ecologically-relevant abiotic gradients (i.e., gradients in temperature, precipitation, elevation, and relative sea-level rise). Our analyses identify areas with high SET-MH station densities as well as areas with notable gaps. Salt marshes, intermediate elevations, and colder areas with high rainfall have a high number of stations, while salt flat ecosystems, certain elevation zones, the mangrove-marsh ecotone, and hypersaline coastal areas with low rainfall have fewer stations. Due to rapid rates of wetland loss and relative sea-level rise, the state of Louisiana has the most extensive SET-MH station network in the region, and we provide several recent examples where data from Louisiana's network have been used to assess and compare wetland vulnerability to sea-level rise. Our findings represent the first attempt to examine spatial gaps in SET-MH coverage across abiotic gradients. Our analyses can be used to transform a broadly disseminated and unplanned collection of SET-MH stations into a coordinated and strategic regional network. This regional network would provide data for predicting and preparing for the responses of coastal wetlands to accelerated sea-level rise and other aspects of global change