SUMMARY The genetic basis of cognition and behavioral adaptation to the environment remains poorly understood. Here we demonstrate that the histone methyltransferase complex GLP/G9a controls cognition and adaptive responses in a region-specific fashion in the adult brain. Using conditional mutagenesis in mice, we show that postnatal, neuron-specific deficiency of GLP/G9a leads to de-repression of numerous non-neuronal and neuron progenitor genes in adult neurons. This transcriptional alteration is associated with complex behavioral abnormalities, including defects in learning, motivation and environmental adaptation. The behavioral changes triggered by GLP/G9a deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with structural alterations of the GLP gene. The likely causal role of GLP/G9a in mental retardation in mice and humans suggests a key role for the GLP/G9a controlled histone H3K9 di-methylation in regulation of brain function through maintenance of the transcriptional homeostasis in adult neurons.

Cocaine is a highly addictive drug that exerts its effects by increasing the levels of released dopamine in the striatum, followed by stable changes in gene transcription, mRNA translation, and metabolism within medium spiny neurons in the striatum. The multiple changes in gene and protein expression associated with cocaine addiction suggest the existence of a mechanism that facilitates a coordinated cellular response to cocaine. Here, we provide evidence for a key role of miRNAs in cocaine addiction. We show that Argonaute 2 (Ago2), which plays an important role in miRNA generation and execution of miRNA-mediated gene silencing, is involved in regulation of cocaine addiction. Deficiency of Ago2 in dopamine 2 receptor (Drd2)–expressing neurons greatly reduces the motivation to self-administer cocaine in mice. We identified a distinct group of miRNAs that is specifically regulated by Ago2 in the striatum. Comparison of miRNAs affected by Ago2 deficiency with miRNAs that are enriched and/or up-regulated in Drd2-neurons in response to cocaine identified a set of miRNAs that are likely to play a role in cocaine addiction.

Cocaine is a highly addictive drug that exerts its effects by increasing the levels of released dopamine in the striatum, followed by stable changes in gene transcription, mRNA translation, and metabolism within medium spiny neurons in the striatum. The multiple changes in gene and protein expression associated with cocaine addiction suggest the existence of a mechanism that facilitates a coordinated cellular response to cocaine. Here, we provide evidence for a key role of miRNAs in cocaine addiction. We show that Argonaute 2 (Ago2), which plays an important role in miRNA generation and execution of miRNA-mediated gene silencing, is involved in regulation of cocaine addiction. Deficiency of Ago2 in dopamine 2 receptor (Drd2)-expressing neurons greatly reduces the motivation to self-administer cocaine in mice. We identified a distinct group of miRNAs that is specifically regulated by Ago2 in the striatum. Comparison of miRNAs affected by Ago2 deficiency with miRNAs that are enriched and/or up-regulated in Drd2-neurons in response to cocaine identified a set of miRNAs that are likely to play a role in cocaine addiction.

SUMMARY The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.

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