Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.

Abrar Qurashi

Shuang Chang

Peng Jin

Role of microRNA Pathway in Mental Retardation

What is the protein apparatus required for microRNA (miRNA) function and translational repression in neurons? This article reviews our recent work on Me31B, a conserved P-body protein present on Staufen-containing neuronal and maternal ribonucleoprotein (RNP) particles, which is required for dendrite morphogenesis and miRNA function in vivo. In addition, it provides new data to show that Me31B is present on and regulates formation of P-bodies in the Drosophila wing disc, where it has a general role in the regulation of miRNA function. While illuminating the function of this important RNA regulatory molecule, it also brings into focus a hypothesis of potentially broad significance. Namely, that P-body proteins may play important roles in regulation of dendrite-localized mRNAs and, thereby, in synaptic plasticity. A wide range of protein localization and early functional data support this hypothesis. We also discuss current knowledge of RNP particles that mediate translational repression and the implications of these findings for understanding translational control in neurons.

Jens Hillebrand

Scott A. Barbee

Mani Ramaswami

P-Body Components, microRNA Regulation, and Synaptic Plasticity

Da-Yu Wu

John S. Saterlee

Decoding Drug Abuse in Noncoding RNA?

The deconstruction of vulnerability to complex disease with the help of intermediate phenotypes, including the heritable and disease-associated endophenotypes, is a legacy of Henri Begleiter. Systematic searches for genes influencing complex disorders, including bipolar disorder, have recently been completed using whole genome association (WGA), identifying a series of validated loci. Using this information, it is possible to compare effect sizes of disease loci discovered in very large samples to the effect sizes of replicated functional loci determining intermediate phenotypes that are of essential interest in psychiatric disorders. It is shown that the genes influencing intermediate phenotypes tend to have a larger effect size. Furthermore, the WGA results reveal that the number of loci of large effect size for complex diseases is limited, and yet multiple functional loci have already been identified for intermediate phenotypes relevant to psychiatric diseases, and without the benefit of WGA.

David Goldman

Francesca Ducci

Deconstruction of Vulnerability to Complex Diseases: Enhanced Effect Sizes and Power of Intermediate Phenotypes

Morphine and related opiates are commonly used in the clinical management of various types of pain. However, the antinociceptive properties of morphine are often overshadowed by the development of tolerance and dependence following its chronic use. The mechanisms underlying opiate tolerance are not fully understood, but appear to involve numerous and complex physiological adaptations. Recently, a role for the heterodimerization of mu and delta opioid receptors in the development of morphine tolerance has been proposed. This novel mechanism could help us to understand several observations, such as the critical role of delta opioid receptor regulation, the impact of delta opioid receptor binding site occupancy, and the participation of beta-arrestin2, in the development of morphine tolerance.

Raphael Rozenfeld

Noura S. Abul-Husn

Ivone Gomez

Lakshmi A. Devi

An Emerging Role for the Delta Opioid Receptor in the Regulation of Mu Opioid Receptor Function

Compulsive cocaine use is associated with a profound dysregulation of sleep. Perhaps the result of chronic use, a significant deterioration in sleep is apparent over the first 3 weeks of abstinence, with no indication of recovery. Interestingly, the diminished sleep is not accompanied by subjective reports of poor or worsening sleep. Rather, subjective reports actually improve over abstinence, while sleep-related cognitive performance declines. A mechanistic understanding of the apparent difference in objective and subjective measures is currently lacking. Here we review the relevant literature on cocaine use and sleep, and discuss the possible relevance of this sleep disturbance in relationship to the underlying disorder and its treatment.

Peter T. Morgan

Robert T. Malison

Cocaine and Sleep: Early Abstinence

Sergi Ferré

Heteromerization of G-Protein–Coupled Receptors. Implications for Central Nervous System Function and Dysfunction

Susan F. Volman

Evaluating the Functional Importance of Neuroadaptions in Addiction

Though accumulating evidence shows that the metabotropic glutamate receptor 5 (mGluR5) mediates some of the actions of extracellular glutamate after cocaine use, the cellular events underlying this action are poorly understood. In this review, we will discuss recent results showing that mGluR5 receptors are key regulators of astrocyte activity. Synaptic release of glutamate activates mGluR5 expressed in perisynaptic astrocytes and generates intense Ca2+ signaling in these cells. Ca2+ oscillations, in turn, trigger the release from astrocytes of the gliotransmitter glutamate, which modulates neuronal excitability by activating NMDA receptors. By integrating these results with the most recent evidence demonstrating the importance of astrocytes in the regulation of neuronal excitability, we propose that astrocytes are involved in mediating some of the mGluR5-dependent drug-induced behaviors.

Tommaso Fellin

Marcello D'Ascenzo

Philip G. Haydon

Astrocytes Control Neuronal Excitability in the Nucleus Accumbens

Bernice Porjesz

Ting-Kai Li

Impulsivity and Addiction: A Tribute to Henri Begleiter

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