Local Control: Dendritic BC1 RNA Regulates Dopamine Receptor Levels

The brain-specific noncoding cytoplasmic RNA BC1 localizes to dendrites, where it is thought to regulate the translation of specific messenger RNAs. By modulating local protein synthesis, the theory goes, BC1 and similar RNAs could shape synapse structure and function. New results from Claudia Bagni and colleagues at the Universita Tor Vergata in Rome, Italy, put that theory on solid ground, by showing that BC1 suppresses D2 dopamine receptor levels and transmission in mouse striatum. The findings suggest that BC1 could be involved in physiological or pathological changes in striatal dopamine transmission, and provide evidence for the importance of localized regulatory RNAs in neuron function. The paper appears in the August 15 issue of the Journal of Neuroscience.

To look at the role of BC1 in dopamine signaling, first authors Diego Centonze and Silvia Rossi utilized BC1-knockout mice, which show behavioral changes indicating possible alterations in striatal function (Lewejohann et al., 2004). The investigators treated cortical slices from wild-type and knockout mice with the D2 agonist quinpirole and then measured GABA-mediated evoked inhibitory postsynaptic currents (eIPSCs) in the striatum as an indicator of dopamine sensitivity. In control mice, quinpirole treatment resulted in reduced eIPSCs, and this effect was enhanced in slices from knockout mice. A similar increase in dopamine sensitivity was apparent when the investigators measured another GABA-dependent response, miniIPSCs. The effects were specific for D2 dopamine receptor transmission, they showed.

How does BC1 affect dopamine transmission? Evidence points to BC1 in complex with the Fragile X mental retardation protein (FMRP), acting as a translational regulator of select dendritic RNAs (Zalfa et al., 2003), raising the possibility that BC1 might repress dopamine receptor protein synthesis. Consistent with this idea, the researchers found BC1 in axons of GABAergic striatal neurons. However, when they looked directly at D2 dopamine receptor mRNA, they found no difference in striatal steady-state mRNA levels or translation efficiency between wild-type or knockout mice. Nonetheless, receptor protein levels were significantly increased nearly twofold. After quinpirole stimulation, the knockout mice had more cell surface D2 receptor. Apparently, FMRP was not involved in the effects of BC1 on the D2 receptor, since brain slices from FMRP knockout mice maintained a normal response to quinpirole. Therefore, while BC1 knockout increased D2 receptor levels, how this happens remains unclear.

The work supports the emerging idea that local RNAs are critical modulators of synapse function. BC1 could figure in the synaptic changes that occur in neurodegenerative conditions featuring dopaminergic dysfunctions, notably Parkinson disease and Huntington disease. For AD, it’s worth noting a recent paper that found overexpression of BC200, a brain-specific, dendritically localized RNA related to BC1, in AD-affected brain tissue (Mus et al., 2007).—Pat McCaffrey

Comments

  1. The Brain Cytoplasmic RNA BC1 Regulates Dopamine D2 Receptor Mediated Transmission in the Striatum
    The work performed by Centonze et al. (Centonze et al., 2007) identifies BC1 RNA as a regulator of dopamine (DA) transmission in the striatum. Interestingly, the fact that BC1 can modulate D2 receptors strongly implies that deregulation of the expression levels of BC1 RNA could alter DA transmission.

    It is known that motor activity and cognition are regulated to a certain extent by ordered DA transmission, and that several neurological and psychiatric conditions are due to alterations in DA D2 receptor signaling. For instance, in Parkinson disease, the second most common neurological disorder, reduced sensitivity of the D2 receptor has been reported, and one could hypothesize that downregulation of BC1 RNA could improve this condition by enhancing the functional response of the D2 receptor. It would, for instance, be interesting to see whether the reduced sensitivity of striatal D2DR in the DJ-1 knockout mouse model for familial Parkinson disease as described by Goldberg et al. (Goldberg et al., 2003) would be ameliorated if these mice were to be crossed to the BC1 KO mice.

    Additionally, one could also consider that the overexpression of BC1 RNA could lead to downregulation of the functional response of the D2 receptor, and this approach could be used to improve psychiatric conditions, such as schizophrenia.

    In conclusion, the identification of BC1 RNA as a regulator of the functional response of the D2 receptor could open up new avenues in pursuit of identifying novel therapeutic targets for these neurological disorders.

    References:

    Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci. 2007 Aug 15;27(33):8885-92. PubMed.

    Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron. 2005 Feb 17;45(4):489-96. PubMed.

    View all comments by Vanessa Morais

  2. The thrust of this paper is that the noncoding RNA BC1 is responsible for regulating D2-mediated synaptic transmission. Perhaps the greatest strength of the study is the robust neurophysiology and pharmacology with tight controls. That data set shows, using corticostriatal slice preparations, that the dopaminergic perturbation (hypersensitivity) is specific for the D2 receptor in BC1-knockout mice. This is especially important in light of the “anxiety” phenotype these mice express, and the probable role(s) of striatal dopamine in human psychiatric diseases. The authors then show that BC1 is apparently present in axons and in striatal GABAergic cells.

    A challenge for this work is that the actual mechanism by which BC1 works is as yet poorly understood. That BC1 may be present in axons has been shown previously; however, the significance of axonal BC1 remains obscure. The authors show that D2DR mRNA and protein levels are not dramatically decreased (protein appears increased) in the BC1 KO mice, and thus conclude that “D2DR-mediated transmission in this brain area is under the control of BC1 RNA, through a process likely to be mediated by a negative influence on D2DR insertion, turnover, and/or stability.”

    The subject matter is complex. It relates to the diverse fields of noncoding RNA, synaptic regulation, dopamine pharmacology and physiology, transgenic mice, cell biology, and translational regulation in neurons. Few investigators are expert in all of these fields, and I tip my cap to these authors for undertaking the challenge. In a general sense, they have added another piece to the amazing puzzle of noncoding RNA biology. More specifically, they demonstrate expertise and a possibly ideal model to tease out the complex mechanism of the brain-enriched noncoding RNA termed BC1.

    View all comments by Peter Nelson

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References

Paper Citations

  1. Lewejohann L, Skryabin BV, Sachser N, Prehn C, Heiduschka P, Thanos S, Jordan U, Dell'Omo G, Vyssotski AL, Pleskacheva MG, Lipp HP, Tiedge H, Brosius J, Prior H. Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behav Brain Res. 2004 Sep 23;154(1):273-89. PubMed.
  2. Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell. 2003 Feb 7;112(3):317-27. PubMed.
  3. Mus E, Hof PR, Tiedge H. Dendritic BC200 RNA in aging and in Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10679-84. PubMed.

Further Reading

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Primary Papers

  1. Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci. 2007 Aug 15;27(33):8885-92. PubMed.

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