Abstract
In the rodent brain, certain G protein-coupled receptors and adenylyl cyclase type 3 are known to localize to the neuronal primary cilium, a primitive sensory organelle protruding singly from almost all neurons. A recent chemical screening study demonstrated that many compounds targeting dopamine receptors regulate the assembly of Chlamydomonas reinhardtii flagella, structures which are analogous to vertebrate cilia. Here we investigated the effects of dopaminergic inputs loss on the architecture of neuronal primary cilia in the rodent striatum, a brain region that receives major dopaminergic projections from the midbrain. We first analyzed the lengths of neuronal cilia in the dorsolateral striatum of hemi-parkinsonian rats with unilateral lesions of the nigrostriatal dopamine pathway. In these rats, the striatal neuronal cilia were significantly longer on the lesioned side than on the non-lesioned side. In mice, the repeated injection of reserpine, a dopamine-depleting agent, elongated neuronal cilia in the striatum. The combined administration of agonists for dopamine receptor type 2 (D2) with reserpine attenuated the elongation of striatal neuronal cilia. Repeated treatment with an antagonist of D2, but not of dopamine receptor type 1 (D1), elongated the striatal neuronal cilia. In addition, D2-null mice displayed longer neuronal cilia in the striatum compared to wild-type controls. Reserpine treatment elongated the striatal neuronal cilia in D1-null mice but not in D2-null mice. Repeated treatment with a D2 agonist suppressed the elongation of striatal neuronal cilia on the lesioned side of hemi-parkinsonian rats. These results suggest that the elongation of striatal neuronal cilia following the lack of dopaminergic inputs is attributable to the absence of dopaminergic transmission via D2 receptors. Our results provide the first evidence that the length of neuronal cilia can be modified by the lack of a neurotransmitter's input.
Highlights
Almost all vertebrate cells possess an immotile primary cilium, which is a cellular appendage with axonemal microtubules in the center wrapped by a membrane that is continuous with the plasma membrane [1,2]
Adenylyl cyclase type 3 (AC3) [4,5] and a growing number of G protein-coupled receptors (GPCRs) including serotonin receptor type 6 [6], somatostatin receptor type 3 (SSTR3) [7,8], melanin-concentrating hormone receptor 1 (MCHR1) [9], vasoactive intestinal peptide receptor 2 [10], neuropeptide Y family receptors [11] and GPR161 [12] have been found to localize to the primary cilia of neurons
It is likely that G protein/cyclic AMP cascades in neuronal cilia detect and amplify extracellular chemical stimuli in the central nervous system [3,14,15,16,17,18,19]; in other words, the neuronal cilium acts as an extra-synaptic neurotransmission device
Summary
Almost all vertebrate cells possess an immotile primary cilium, which is a cellular appendage with axonemal microtubules in the center wrapped by a membrane that is continuous with the plasma membrane [1,2]. Adenylyl cyclase type 3 (AC3) [4,5] and a growing number of G protein-coupled receptors (GPCRs) including serotonin receptor type 6 [6], somatostatin receptor type 3 (SSTR3) [7,8], melanin-concentrating hormone receptor 1 (MCHR1) [9], vasoactive intestinal peptide receptor 2 [10], neuropeptide Y family receptors [11] and GPR161 [12] have been found to localize to the primary cilia of neurons. It is likely that G protein/cyclic AMP (cAMP) cascades in neuronal cilia detect and amplify extracellular chemical stimuli in the central nervous system [3,14,15,16,17,18,19]; in other words, the neuronal cilium acts as an extra-synaptic neurotransmission device
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