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Targeting Ras/ERK signaling in the striatum: will it help?

Molecular Psychiatry volume 8, pages 366–368 (2003)Cite this article

Research in neuroscience and pharmacology over the last decades has not yet provided us with effective treatments for neuropsychiatric diseases such as Huntington's disease (HD), Alzheimer's disease (AD) or drug addiction. On the other hand, pharmacological targeting of the monoaminergic systems has been proven largely successful in the therapy for Parkinson's disease (PD), schizophrenia, and depression.1,2,3 However, further progress in therapy is hampered by our poor understanding of the cellular effects of the available drugs on neural functions. It is conceivable that while the benefits of long-term systemic treatments are caused by adaptive mechanisms in specific brain areas, at the same time side effects may arise from conflicting synaptic adaptations in the same or other structures. Downstream to neurotransmitters and their receptors, possible cellular candidates implicated in such long-term synaptic changes include signaling components that transduce information to the transcriptional machinery in the cell nucleus, and therefore regulate gene expression. As investigation tool for evaluating whether alterations in these molecular processes within the brain may affect learning processes and behavioral responses in general, the analysis of genetically modified mice has proven to be one of the most successful.

Among others, the striatum is a crucial element in the neural circuitry underlying procedural learning, motor control, and reward.4 Therefore, it is not at all surprising that in a number of neuropsychiatric disorders, including PD and HD, some forms of psychosis and depression, obsessive–compulsive disorders, and drug abuse, significant alterations in the neurobiology of this brain structure have been detected. The development of effective pharmacological means to treat some of these diseases has been paralleled by important progress in the comprehension of the basic neurochemistry of the striatum. While current working models aiming to explain striatal physiology and pathology have focused on the regulation of the main population of striatal cells, the GABAergic medium spiny neurons, by glutamatergic and dopaminergic receptor systems, relevant roles for other receptor systems and minor-population neurons (eg cholinergic ones) have begun to emerge. One of the major questions now is to determine how signal specificity is achieved within neuronal networks in response to such a variety of stimuli. In this sense not only qualitative (‘what molecules are activated’), but also quantitative (‘how much and how long the activation is’) aspects should be taken into account. Recent evidence suggests that the Ras/ERK signaling cascade is an important element regulating plasticity in the striatum, and therefore an interesting candidate for future drug targeting.

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Acknowledgements

I thank Dr Stefania Fasano for artwork and Dr Paul Orban for critically reviewing the manuscript. This work was supported by the European Commission, the Telethon Foundation for Genetic Diseases and the Italian Federation for Cancer Research.

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    R Brambilla

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Brambilla, R. Targeting Ras/ERK signaling in the striatum: will it help?. Mol Psychiatry 8, 366–368 (2003). https://doi.org/10.1038/sj.mp.4001291

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