The 1980s: D-AP5, LTP and a Decade of NMDA Receptor Discoveries.

In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of D-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.

Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model.

An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.

Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine.

A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.

Sarcodon in the Neotropics I: new species from Guyana, Puerto Rico and Belize.

Four species of the ectomycorrhizal (ECM) genus Sarcodon (Bankeraceae, Thelephorales, Basidiomycota) are described as new to science. Sarcodon pakaraimensis sp. nov. is described from forests dominated by the ECM trees Pakaraimaea dipterocarpacea (Dipterocarpaceae) and Dicymbe jenmanii (Fabaceae subfam. Caesalpinioideae) in the Pakaraima Mountains of Guyana. Sarcodon portoricensis sp. nov. is described from lower montane wet forest within the El Yunque National Forest of Puerto Rico. Sarcodon quercophilus sp. nov. and Sarcodon umbilicatus sp. nov. are described from Quercus (Fagaceae) cloud forests within the Maya Mountains of Belize. The discovery of these species is significant given that the majority of the approximately 87 described Sarcodon species are north temperate or boreal in distribution and frequently associate with coniferous host plants; these constitute the most recent records for Sarcodon from the greater Neotropics. Each of the new species is morphologically consistent with accepted diagnostic characters for Sarcodon: pileate-stipitate stature, a dentate hymenophore, determinate basidiomatal development, fleshy, non-zonate context and brown, tuberculate basidiospores. DNA (ITS) sequence analysis corroborated the generic placement of S. pakaraimensis, S. portoricensis, S. quercophilus and S. umbilicatus and, along with morphological differences, supported their recognition as distinct species. Macromorphological, micromorphological, habitat and DNA sequence data from the nuc rDNA internal transcribed spacer region (ITS) are provided for each of the new species. A key to Neotropical Sarcodon species and similar extralimital taxa is provided.

Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia.

Schizophrenia patients exhibit increased hippocampal activity that is correlated with positive symptoms. Although the cause of this hippocampal hyperactivity has not been demonstrated, it likely involves a decrease in GABAergic signaling. Thus, we posit that restoring GABAergic function may provide a novel therapeutic approach for the treatment of schizophrenia. It has been demonstrated that transplanted GABAergic precursor cells from the medial ganglionic eminence (MGE) can migrate and differentiate into mature interneurons. Here, we demonstrate that ventral hippocampal MGE transplants can restore hippocampal function and normalize downstream dopamine neuron activity in a rodent model of schizophrenia. Furthermore, MGE transplants also reverse the hyper-responsive locomotor response to amphetamine. Taken together, these data demonstrate that restoring interneuron function reverses neurophysiological and behavioral deficits in a rodent model of schizophrenia and moreover, demonstrate the feasibility of a neuronal transplant procedure as a potential novel therapeutic approach for the treatment of schizophrenia.

Evolutionary consequences of putative intra-and interspecific hybridization in agaric fungi.

Agaric fungi of the southern Appalachian Mountains including Great Smoky Mountains National Park are often heterozygous for the rDNA internal transcribed spacer region (ITS) with >42% of collections showing some heterozygosity for indels and/or base-pair substitutions. For these collections, intra-individual haplotype divergence is typically less than 2%, but for 3% of these collections intra-individual haplotype divergence exceeds that figure. We hypothesize that high intra-individual haplotype divergence is due to hybridization between agaric fungi with divergent haplotypes, possibly migrants from geographically isolated glacial refugia. Four species with relatively high haplotype divergence were examined: Armillaria mellea, Amanita citrina f. lavendula, Gymnopus dichrous and the Hygrocybe flavescens/chlorophana complex. The ITS region was sequenced, haplotypes of heterozygotes were resolved through cloning, and phylogenetic analyses were used to determine the outcome of hybridization events. Within Armillaria mellea and Amanita citrina f. lavendula, we found evidence of interbreeding and recombination. Within G. dichrous and H. flavescens/chlorophana, hybrids were identified but there was no evidence for F2 or higher progeny in natural populations suggesting that the hybrid fruitbodies might be an evolutionary dead end and that the genetically divergent Mendelian populations from which they were derived are, in fact, different species. The association between ITS haplotype divergence of less than 5% (Armillaria mellea = 2.6% excluding gaps; Amanita citrina f. lavendula = 3.3%) with the presence of putative recombinants and greater than 5% (Gymnopus dichrous = 5.7%; Hygrocybe flavescens/chlorophana = 14.1%) with apparent failure of F1 hybrids to produce F2 or higher progeny in populations may suggest a correlation between genetic distance and reproductive isolation.

Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala.

The leptin receptor (Lepr) is expressed on midbrain dopamine neurons. However, the specific role of Lepr signaling in dopamine neurons remains to be clarified. In the present study, we generated a line of conditional knockout mice lacking functional Lepr selectively on dopamine neurons (Lepr(DAT-Cre)). These mice exhibit normal body weight and feeding. Behaviorally, Lepr(DAT-Cre) mice display an anxiogenic-like phenotype in the elevated plus-maze, light-dark box, social interaction and novelty-suppressed feeding tests. Depression-related behaviors, as assessed by chronic stress-induced anhedonia, forced swim and tail-suspension tests, were not affected by deletion of Lepr in dopamine neurons. In vivo electrophysiological recordings of dopamine neurons in the ventral tegmental area revealed an increase in burst firing in Lepr(DAT-Cre) mice. Moreover, blockade of D1-dependent dopamine transmission in the central amygdala by local microinjection of the D1 antagonist SCH23390 attenuated the anxiogenic phenotype of Lepr(DAT-Cre) mice. These findings suggest that Lepr signaling in midbrain dopamine neurons has a crucial role for the expression of anxiety and for the dopamine modulation of amygdala function.

A Preconditioning Paradox: Contrasting Effects of Initial Phyllosphere and Early Leaf Decomposer Microfungi on Subsequent Colonization by Leaf Decomposing Non-Unit-Restricted Basidiomycetes.

Fungal interactions during leaf decomposition can facilitate or inhibit other fungi. This experiment focused on whether preconditioning of leaf litter by microfungi that were confined to one leaf (Unit-Restricted) made leaf litter less likely to be colonized and decomposed by basidiomycetes that bind litter into mats (Non-Unit-Restricted) than non-preconditioned litter. Leaves of Manilkara bidentata in litterbags were preconditioned by incubating them for 0, 1, 2 or 3 months in flat litter/seed rain baskets 10 cm above the forest floor to avoid colonization by basidiomycete fungi. Preconditioned and non-preconditioned leaves were transferred to 5 replicate basidiomycete fungal mats of Gymnopus johnstonii for 6 weeks. Both attachment by basidiomycete fungi and percent mass loss after 6 weeks decreased significantly with increasing preconditioning time. In non-preconditioned leaves, gamma irradiation did not affect mass loss or percent white-rot despite having significantly increased numbers of basidiomycete fungal connections as compared to non-irradiated leaves. In non-preconditioned leaves, more basidiomycetes attachmented to non-irradiated than irradiated leaves suggest facilitation by phyllosphere microfungi. While basidiomycete colonization was initially facilitated by phyllosphere fungi, we inferred that degradation of resource quality led to fewer fungal attachments and less mass loss after 1-3 months of preconditioning by microfungi. The date suggest there is a 1-month time window for basidiomycete fungi to incorporate fallen leaves into their litter mats.

A new Cantharocybe from Belize with notes on the type of Cantharocybe gruberi.

A new species of Cantharocybe, C. brunneovelutina, is described and illustrated from the Orange Walk District of Belize. The species is characterized by the subvelutinous brown pileus, brownish gray stipe and microscopically by cheilocystidia that have prong-like appendages. Analysis of nLSU rDNA sequences relates this species to Cantharocybe gruberi, the sole member of a previously monotypic genus of uncertain placement. We also provide a microscopic description and illustrations of the type collection of Cantharocybe gruberi and compare the two species. Morphological comparisons among Cantharocybe and its sister genus, Cuphophyllus (= Camarophyllus), and allied genera are discussed.

Ancestral predisposition toward a domesticated lifestyle in the termite-cultivated fungus Termitomyces.

The ancestor of termites relied on gut symbionts for degradation of plant material, an association that persists in all termite families.1,2 However, the single-lineage Macrotermitinae has additionally acquired a fungal symbiont that complements digestion of food outside the termite gut.3 Phylogenetic analysis has shown that fungi grown by these termites form a clade-the genus Termitomyces-but the events leading toward domestication remain unclear.4 To address this, we reconstructed the lifestyle of the common ancestor of Termitomyces using a combination of ecological data with a phylogenomic analysis of 21 related non-domesticated species and 25 species of Termitomyces. We show that the closely related genera Blastosporella and Arthromyces also contain insect-associated species. Furthermore, the genus Arthromyces produces asexual spores on the mycelium, which may facilitate insect dispersal when growing on aggregated subterranean fecal pellets of a plant-feeding insect. The sister-group relationship between Arthromyces and Termitomyces implies that insect association and asexual sporulation, present in both genera, preceded the domestication of Termitomyces and did not follow domestication as has been proposed previously. Specialization of the common ancestor of these two genera on an insect-fecal substrate is further supported by similar carbohydrate-degrading profiles between Arthromyces and Termitomyces. We describe a set of traits that may have predisposed the ancestor of Termitomyces toward domestication, with each trait found scattered in related taxa outside of the termite-domesticated clade. This pattern indicates that the origin of the termite-fungus symbiosis may not have required large-scale changes of the fungal partner.

Luminescent Mycena: new and noteworthy species.

Seven species of Mycena are reported as luminescent, representing specimens collected in Belize, Brazil, Dominican Republic, Jamaica, Japan (Bonin Islands), Malaysia (Borneo) and Puerto Rico. Four of them represent new species (Mycena luxaeterna, M. luxarboricola, M. luxperpetua, M. silvaelucens) and three represent new reports of luminescence in previously described species (M. aff. abieticola, M. aspratilis, M. margarita). Mycena subepipterygia is synonymized with M. margarita, and M. chlorinosma is proposed as a possible synonym. Comprehensive descriptions, illustrations, photographs and comparisons with phenetically similar species are provided. A redescription of M. chlorophos, based on analyses of type specimens and recently collected topotypical material, is provided. The addition of these seven new or newly reported luminescent species of Mycena brings the total to 71 known bioluminescent species of fungi.

New species and reports of Cuphophyllus from northern North America compared with related Eurasian species.

This study describes four gray or brown species of Cuphophyllus (Hygrophoraceae, Agaricales), two of them new species, restricted to arctic-alpine and northern boreal zones of North America, and relates them morphologically and phylogenetically using multigene and nuc rDNA internal transcribed spacer ITS1-5.8S-ITS (ITS barcode) analyses to their similar, known counterparts. Cuphophyllus cinerellus, epitypified here, is shown to be a pan-palearctic species with sequence-confirmed collections from Fennoscandia and easternmost Asia. Occupying a similar habitat in the Nearctic is its sister species, the morphologically similar but novel C. esteriae, so far known only from eastern North America, including Greenland. Sister to the C. cinerellus-C. esteriae lineage, and known only from boreal raised Sphagnum bogs in Newfoundland, is a new medium-sized light cinereous brown species, C. lamarum. It has a yellow stipe but is phylogenetically distant from the yellow-stiped European C. flavipes and its North American sister species, Hygrophorus pseudopallidus. As cryptic speciation was discovered within C. flavipes, we lecto- and epitypify the name and transfer H. pseudopallidus to Cuphophyllus based on ITS analysis of the holotype. We also transfer the small European Hygrocybe comosa to Cuphophyllus based on morphology. Cuphophyllus hygrocyboides is reported from North America with the first sequence-confirmed collections from arctic-alpine British Columbia and Greenland. In addition, sequencing the holotype of C. subviolaceus identifies it as the sister species to the putative C. lacmus. Both species seem to have an intercontinental distribution. In total, we add new sequences to GenBank from 37 Cuphophyllus collections, including the holotypes of C. hygrocyboides and C. subviolaceus, the two new epitypes, and the two novel species.

Studies of Neotropical tree pathogens in Moniliophthora: a new species, M. mayarum, and new combinations for Crinipellis ticoi and C. brasiliensis.

The crinipelloid genera Crinipellis and Moniliophthora (Agaricales, Marasmiaceae) are characterized by basidiomes that produce long, dextrinoid, hair-like elements on the pileus surface. Historically, most species are believed to be saprotrophic or, rarely, parasitic on plant hosts. The primary morphological diagnostic characters that separate Crinipellis and Moniliophthora are pliant vs. stiff (Crinipellis) stipes and a tendency toward production of reddish pigments (ranging from violet to orange) in the basidiome in Moniliophthora. Additionally, most species of Moniliophthora appear to have a biotrophic habit, while those of Crinipellis are predominantly saprotrophic. Recently, several new neotropical collections prompted a morphological and phylogenetic analysis of this group. Herein, we propose a new species and two new combinations: Moniliophthora mayarum sp. nov., described from Belize, is characterized by its larger pileus and narrower basidiospores relative to other related species; Moniliophthora ticoi comb. nov. (= Crinipellis ticoi) is recollected and redescribed from biotrophic collections from northern Argentina; and M. brasiliensis comb. nov. (= Crinipellis brasiliensis), a parasite of Heteropterys acutifolia. The addition of these three parasitic species into Moniliophthora support a hypothesis of a primarily biotrophic/parasitic habit within this genus.

Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists.

The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.

Ecological forecasts: an emerging imperative.

Planning and decision-making can be improved by access to reliable forecasts of ecosystem state, ecosystem services, and natural capital. Availability of new data sets, together with progress in computation and statistics, will increase our ability to forecast ecosystem change. An agenda that would lead toward a capacity to produce, evaluate, and communicate forecasts of critical ecosystem services requires a process that engages scientists and decision-makers. Interdisciplinary linkages are necessary because of the climate and societal controls on ecosystems, the feedbacks involving social change, and the decision-making relevance of forecasts.

Global biodiversity scenarios for the year 2100.

Scenarios of changes in biodiversity for the year 2100 can now be developed based on scenarios of changes in atmospheric carbon dioxide, climate, vegetation, and land use and the known sensitivity of biodiversity to these changes. This study identified a ranking of the importance of drivers of change, a ranking of the biomes with respect to expected changes, and the major sources of uncertainties. For terrestrial ecosystems, land-use change probably will have the largest effect, followed by climate change, nitrogen deposition, biotic exchange, and elevated carbon dioxide concentration. For freshwater ecosystems, biotic exchange is much more important. Mediterranean climate and grassland ecosystems likely will experience the greatest proportional change in biodiversity because of the substantial influence of all drivers of biodiversity change. Northern temperate ecosystems are estimated to experience the least biodiversity change because major land-use change has already occurred. Plausible changes in biodiversity in other biomes depend on interactions among the causes of biodiversity change. These interactions represent one of the largest uncertainties in projections of future biodiversity change.

Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner.

Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Here we attempt to reverse this deficit by overexpression of the α5-GABAA receptor within the ventral hippocampus (vHipp). Indeed, this is sufficient to normalize vHipp activity and downstream alterations in dopamine neuron function in the MAM rodent model. This approach also attenuated behavioral deficits in cognitive flexibility. To understand the specific pathways that mediate these effects, we used chemogenetics to manipulate discrete projections from the vHipp to the nucleus accumbens (NAc) or prefrontal cortex (mPFC). We found that inhibition of the vHipp-NAc, but not the vHipp-mPFC pathway, normalized aberrant dopamine neuron activity. Conversely, inhibition of the vHipp-mPFC improved cognitive function. Taken together, these results demonstrate that restoring GABAergic signaling in the vHipp improves schizophrenia-like deficits and that distinct behavioral alterations are mediated by discrete projections from the vHipp to the NAc and mPFC.

A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP.

The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the kainate receptor antagonist LY382884 (10 microM) is selective for presynaptic kainate receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic kainate receptor that facilitates AMPA receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic kainate receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic kainate receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which kainate receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.

Four new species of Morchella from the Americas.

Morphological and molecular phylogenetic studies of true morels (Morchella) in North America, the Dominican Republic, Venezuela, Ecuador, and Peru led to the discovery of four undescribed species of Morchella. Two new species in the Elata clade, one from the Dominican Republic, initially distinguished by the informal designation Mel-18, and a newly discovered sister species from northern Arizona, are now recognized. Mel-18 is described as a novel phylogenetically distinct species, M. hispaniolensis. Its sister species from Arizona is described as M. kaibabensis, also recovered as an endophyte of Rocky Mountain juniper. Two additional species in the Esculenta clade, M. peruviana discovered in Peru and M. gracilis (previously reported as Mes-14) from the Dominican Republic, Venezuela, and Ecuador, are described as new. We also demonstrate that scanning electron microscopy (SEM) imaging of ascospores using rehydration/dehydration/critical point drying preparation techniques provides for enhanced resolution of spore wall surfaces, thereby increasing the number of morphological traits available to assess differences among otherwise closely related species.

Major clades of Agaricales: a multilocus phylogenetic overview.

An overview of the phylogeny of the Agaricales is presented based on a multilocus analysis of a six-gene region supermatrix. Bayesian analyses of 5611 nucleotide characters of rpb1, rpb1-intron 2, rpb2 and 18S, 25S, and 5.8S ribosomal RNA genes recovered six major clades, which are recognized informally and labeled the Agaricoid, Tricholomatoid, Marasmioid, Pluteoid, Hygrophoroid and Plicaturopsidoid clades. Each clade is discussed in terms of key morphological and ecological traits. At least 11 origins of the ectomycorrhizal habit appear to have evolved in the Agaricales, with possibly as many as nine origins in the Agaricoid plus Tricholomatoid clade alone. A family-based phylogenetic classification is sketched for the Agaricales, in which 30 families, four unplaced tribes and two informally named clades are recognized.