Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar inhibitory interneurons.
ABSTRACT 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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ABSTRACT: Neuropeptide Y (NPY) is widely expressed throughout the nervous system and is known to reduce excitatory (but also inhibitory) synaptic transmission in many CNS areas, leading to the proposal that it is an endogenous antiepileptic agent. In the neocortex, where NPY is present in gamma-aminobutyric acid (GABA)ergic interneurons, its effects on inhibitory and excitatory synaptic activities have not been completely explored. Here we report that NPY application elicits a long-lasting decrease in evoked excitatory postsynaptic current amplitude and a delayed, long-lasting increase in the amplitude of evoked monosynaptic inhibitory postsynaptic current (IPSC) in layer V pyramidal neurons of rat neocortex. The novel, late, NPY-mediated increase of inhibitory synaptic transmission is caused by modulation of Ca2+-dependent GABA release onto pyramidal neurons, as it was accompanied by an increase in Ca2+-dependent miniature IPSC frequency. NPY decreased evoked monosynaptic IPSCs in GABAergic interneurons, indicating that this neuropeptide has differential effects on different neuronal subtypes in the neocortex. Each of these NPY actions would decrease excitability in cortical circuits, a result that has important implications for both physiological neocortical operations as well as pathophysiological epileptiform activities.Proceedings of the National Academy of Sciences 01/2003; 99(26):17125-30. · 9.74 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) mediates its physiological effects through at least four receptors known as Y(1), Y(2), Y(4), and Y(5). This peptide is one of the most abundant peptides in the central nervous system and is highly conserved throughout evolution. The most abundant receptors of the NPY family, the Y(1) and Y(2) receptors, are densely expressed in the cortex, hippocampus, and amygdala. These brain regions are particularly associated with mood disorders, stress responses, and memory processing. With this in mind, researchers suggested the involvement of NPY as well as the Y(1) and Y(2) receptors in affective disorders. Earlier studies showed that NPY and the Y(1) and Y(2) receptors mediate some aspects of depression-like disorders and stress responses in rodents. Recent research also suggests the involvement of the Y(4) and Y(5) receptors in emotion-related processes in rodents. In addition, human studies have consistently suggested a role for NPY in stress responses, whereas conflicting data have been obtained in relation to the role of NPY in depression-related illnesses. However, novel evidence from polymorphisms in the prepro-NPY gene has shed new light on the potential clinical relevance of NPY in depression. In this article, we review the literature from both animal and human studies regarding the contribution of NPY and its receptors in depression and stress.Brain research 09/2009; 1314:194-205. · 2.46 Impact Factor
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ABSTRACT: Light microscopic immunocytochemistry for neuropeptide Y (NPY) has demonstrated the presence of a diffuse system of NPY-immunoreactive fibers in the cerebellum of Myotis lucifugus. These fibers gain access to the cerebellum by way of the superior cerebellar peduncle, and terminate on Purkinje cell dendrites and on neurons in the granule cell layer. The origin of cerebellar NPY and possible colocalization with norepinephrine are discussed.Neuroscience Letters 02/1991; 122(1):25-8. · 2.03 Impact Factor