Tu B, Jiao Y, Herzog H, Nadler J V
Department of Pharmacology and Cancer Biology, Duke University Medical Center, PO Box 3813, 100B Research Park 2, Research Drive, Durham, NC 27710, USA.
Neuroscience. 2006 Dec 28;143(4):1085-94. doi: 10.1016/j.neuroscience.2006.08.036. Epub 2006 Oct 4.
A unique feature of temporal lobe epilepsy is the formation of recurrent excitatory connections among granule cells of the dentate gyrus as a result of mossy fiber sprouting. This novel circuit contributes to a reduced threshold for granule cell synchronization. In the rat, activity of the recurrent mossy fiber pathway is restrained by the neoexpression and spontaneous release of neuropeptide Y (NPY). NPY inhibits glutamate release tonically through activation of presynaptic Y2 receptors. In the present study, the effects of endogenous and applied NPY were investigated in C57Bl/6 mice that had experienced pilocarpine-induced status epilepticus and subsequently developed a robust recurrent mossy fiber pathway. Whole cell patch clamp recordings made from dentate granule cells in hippocampal slices demonstrated that, as in rats, applied NPY inhibits recurrent mossy fiber synaptic transmission, the Y2 receptor antagonist (S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide (BIIE0246) blocks its action and BIIE0246 enhances synaptic transmission when applied by itself. Y5 receptor agonists had no significant effect. Thus spontaneous release of NPY tonically inhibits synaptic transmission in mice and its effects are mediated by Y2 receptor activation. However, both NPY and BIIE0246 were much less effective in mice than in rats, despite apparently equivalent expression of NPY in the recurrent mossy fibers. Immunohistochemistry indicated greater expression of Y2 receptors in the mossy fiber pathway of normal mice than of normal rats. Pilocarpine-induced status epilepticus markedly reduced the immunoreactivity of mouse mossy fibers, but increased the immunoreactivity of rat mossy fibers. Mossy fiber growth into the inner portion of the dentate molecular layer was associated with increased Y2 receptor immunoreactivity in rat, but not in mouse. These contrasting receptor changes can explain the quantitatively different effects of endogenously released and applied NPY on recurrent mossy fiber transmission in mice and rats.
颞叶癫痫的一个独特特征是，由于苔藓纤维出芽，齿状回颗粒细胞之间形成了反复性兴奋性连接。这种新的神经回路导致颗粒细胞同步化阈值降低。在大鼠中，反复性苔藓纤维通路的活动受到神经肽Y（NPY）新表达和自发释放的抑制。NPY通过激活突触前Y2受体持续抑制谷氨酸释放。在本研究中，我们在经历匹罗卡品诱导的癫痫持续状态并随后形成强大的反复性苔藓纤维通路的C57Bl/6小鼠中，研究了内源性和外源性NPY的作用。对海马切片中齿状颗粒细胞进行的全细胞膜片钳记录表明，与大鼠一样，外源性NPY抑制反复性苔藓纤维突触传递，Y2受体拮抗剂（S）-N2-[[1-[2-[4-[(R,S)-5,11-二氢-6(6H)-氧代二苯并[b,e]氮杂卓-11-基]-1-哌嗪基]-2-氧代乙基]环戊基]乙酰基]-N-[2-[1,2-二氢-3,5(4H)-二氧代-1,2-二苯基-3H-1,2,4-三唑-4-基]乙基]-精氨酰胺（BIIE0246）可阻断其作用，而BIIE0246单独应用时可增强突触传递。Y5受体激动剂无显著作用。因此，NPY的自发释放持续抑制小鼠的突触传递，其作用由Y2受体激活介导。然而，尽管反复性苔藓纤维中NPY的表达明显相当，但NPY和BIIE0246在小鼠中的作用远不如在大鼠中有效。免疫组织化学表明，正常小鼠苔藓纤维通路中Y2受体的表达高于正常大鼠。匹罗卡品诱导的癫痫持续状态显著降低了小鼠苔藓纤维的免疫反应性，但增加了大鼠苔藓纤维的免疫反应性。苔藓纤维向齿状分子层内部生长与大鼠Y2受体免疫反应性增加有关，而与小鼠无关。这些相反的受体变化可以解释内源性释放和外源性应用的NPY对小鼠和大鼠反复性苔藓纤维传递的定量不同影响。
