16 August 2007. 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.
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. Journal of Neuroscience. 2007 Aug 15; 27:8885-8892. Abstract