Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar inhibitory interneurons

Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Journal of Neurophysiology (Impact Factor: 2.89). 12/2011; 107(6):1655-65. DOI: 10.1152/jn.00755.2011
Source: PubMed


Neuropeptide Y (NPY), a widely distributed neuropeptide in the central nervous system, can transiently suppress inhibitory synaptic transmission and alter membrane excitability via Y2 and Y1 receptors (Y2rs and Y1rs), respectively. Although many GABAergic neurons express Y5rs, the functional role of these receptors in inhibitory neurons is not known. Here, we investigated whether activation of Y5rs can modulate inhibitory transmission in cerebellar slices. Unexpectedly, application of NPY triggered a long-lasting increase in the frequency of miniature inhibitory postsynaptic currents in stellate cells. NPY also induced a sustained increase in spontaneous GABA release in cultured cerebellar neurons. When cerebellar cultures were examined for Y5r immunoreactivity, the staining colocalized with that of VGAT, a presynaptic marker for GABAergic cells, suggesting that Y5rs are located in the presynaptic terminals of inhibitory neurons. RT-PCR experiments confirmed the presence of Y5r mRNA in the cerebellum. The NPY-induced potentiation of GABA release was blocked by Y5r antagonists and mimicked by application of a selective peptide agonist for Y5r. Thus Y5r activation is necessary and sufficient to trigger an increase in GABA release. Finally, the potentiation of inhibitory transmission could not be reversed by a Y5r antagonist once it was initiated, consistent with the development of a long-term potentiation. These results indicate that activation of presynaptic Y5rs induces a sustained increase in spontaneous GABA release from inhibitory neurons in contrast to the transient suppression of inhibitory transmission that is characteristic of Y1r and Y2r activation. Our findings thus reveal a novel role of presynaptic Y5rs in inhibitory interneurons in regulating GABA release and suggest that these receptors could play a role in shaping neuronal network activity in the cerebellum.

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    • "Both the NPY 1 Rs and NPY 5 Rs have been reported to mediate the NPY-induced anxiolytic-like activity in the elevated plus maze and open field tests [147]; however, NPY 5 R KO mice display normal function in the elevated plus maze and open field tests [148], suggesting that the NPY 1 R is primarily responsible for the anxiolytic-like phenotype [149]. The NPY 5 R has also been reported to increase spontaneous GABA release from GABAergic neurons, resulting in an induction of inhibitory synaptic transmission [150]. NPY 5 R KO mice exhibit normal learning and memory in the Morris water maze and object recognition tests [148]. "
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