The Lysine Acetyltransferase PCAF Functionally Interacts with Estrogen Receptor Alpha in the Hippocampus of Gonadally Intact Male-But Not Female-Rats to Enhance Short-Term Memory.

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERß agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM.

King or royal family? Testing for species boundaries in the King Cobra, Ophiophagus hannah (Cantor, 1836), using morphology and multilocus DNA analyses.

In widespread species, the diverse ecological conditions in which the populations occur, and the presence of many potential geographical barriers through their range are expected to have created ample opportunities for the evolution of distinct, often cryptic lineages. In this work, we tested for species boundaries in one such widespread species, the king cobra, Ophiophagus hannah (Cantor, 1836), a largely tropical elapid snake distributed across the Oriental realm. Based on extensive geographical sampling across most of the range of the species, we initially tested for candidate species (CS) using Maximum-Likelihood analysis of mitochondrial genes. We then tested the resulting CS using both morphological data and sequences of three single-copy nuclear genes. We used snapclust to determine the optimal number of clusters in the nuclear dataset, and Bayesian Phylogenetics and Phylogeography (BPP) to test for likely species status. We used non-metric multidimensional scaling (nMDS) analysis for discerning morphological separation. We recovered four independently evolving, geographically separated lineages that we consider Confirmed Candidate Species: (1) Western Ghats lineage; (2) Indo-Chinese lineage (3) Indo-Malayan lineage; (4) Luzon Island lineage, in the Philippine Archipelago. We discuss patterns of lineage divergence, particularly in the context of low morphological divergence, and the conservation implications of recognizing several endemic king cobra lineages.

Molecular phylogenetics of sub-Saharan African natricine snakes, and the biogeographic origins of the Seychelles endemic Lycognathophis seychellensis.

Phylogenetic relationships of sub-Saharan African natricine snakes are understudied and poorly understood, which in turn has precluded analyses of the historical biogeography of the Seychelles endemic Lycognathophis seychellensis. We inferred the phylogenetic relationships of Seychelles and mainland sub-Saharan natricines by analysing a multilocus DNA sequence dataset for three mitochondrial (mt) and four nuclear (nu) genes. The mainland sub-Saharan natricines and L. seychellensis comprise a well-supported clade. Two maximally supported sets of relationships within this clade are (Limnophis,Natriciteres) and (Afronatrix,(Hydraethiops,Helophis)). The relationships of L. seychellensis with respect to these two lineages are not clearly resolved by analysing concatenated mt and nu data. Analysed separately, nu data best support a sister relationship of L. seychellensis with (Afronatrix,(Hydraethiops,Helophis)) and mt data best support a sister relationship with all mainland sub-Saharan natricines. Methods designed to cope with incomplete lineage sorting strongly favour the former hypothesis. Genetic variation among up to 33 L. seychellensis from five Seychelles islands is low. Fossil calibrated divergence time estimates support an overseas dispersal of the L. seychellensis lineage to the Seychelles from mainland Africa ca. 43-25 million years before present (Ma), rather than this taxon being a Gondwanan relic.

Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein.

Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.

Tracking speakers' false beliefs: is theory of mind available earlier for word learning?

Happé and Loth (2002) describe word learning as a 'privileged domain' in the development of a theory of mind. We test this claim in a series of experiments based on the Sally-Anne paradigm. Three- and 4-year-old children's ability to represent others' false beliefs was investigated in tasks that required the child either to predict the actions of a protagonist in a story or to learn the meaning of a new word used by the protagonist. Experiment 1 replicated previous findings of better performance in a false belief word-learning task compared to a false belief action-prediction task. However, systematic manipulation of the task parameters in Experiments 2 and 3 revealed that this performance discrepancy disappeared when tasks were equated in their 'referential pull' (Perner, Rendl & Garnham, 2007). We conclude that the notion of a precocious theory of mind for word learning is not required to explain dissociations in performance on false belief tasks.