Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice
Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice
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DOI：
10.1523/jneurosci.21-15-05813.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Frens, MA
中科院分区：
文献类型：
--
作者：
Goossens, J;Daniel, H;Frens, MA
一个长期存在但仍然存在争议的假设是，小脑中平行纤维浦肯野细胞突触的长期抑制（LTD）体现了联想运动学习所需的部分神经元信息存储。 LTD 被浦肯野细胞特异性抑制蛋白激酶 C (PKC)（L7-PKCI 突变体）阻断的转基因小鼠确实表现出前庭眼反射适应受损，而其眼球运动表现的动态不受影响。然而，由于 L7-PKCI 突变体至少在 35 天龄之前具有持续的多重攀爬纤维神经支配，并且由于 L7-PKCI 突变体中浦肯野细胞的基线放电未知，因此除 LTD 诱导本身受阻之外的其他因素可能是其运动学习受损的原因。因此，我们研究了警觉的成年 L7-PKCI 小鼠中浦肯野细胞的自发放电以及超过 3 个月龄时的多重攀爬纤维神经支配。我们发现，L7-PKCI 突变体中的简单尖峰和复杂尖峰放电特性（例如平均放电率、尖峰间间隔和尖峰计数变异性）、振荡和攀爬纤维暂停与野生型同窝小鼠没有区别。此外，我们发现从 3 至 6 个月大的突变体获得的小脑切片中并未发生多重攀爬纤维神经支配。这些数据表明（1）PKC 抑制和随后的 LTD 诱导阻断都不会干扰警觉小鼠中浦肯野细胞的自发放电，（2）浦肯野细胞对 PKC 的特异性抑制会延缓而不是阻止浦肯野细胞通过攀爬纤维从多神经支配到单神经支配的发育转变，以及（3）因此，在老年 L7-PKCI 突变体中观察到的运动学习受损不能归因于基线简单尖峰和复合体的干扰浦肯野细胞的尖峰活动或持续的多重攀爬纤维神经支配。我们的结论是，小脑LTD可能是运动学习的主要机制之一，但L7-PKCI突变体中观察到的LTD诱导和运动学习的缺陷可能仅反映在训练期间和/或训练后浦肯野细胞信号的差异上。
A longstanding but still controversial hypothesis is that longterm depression (LTD) of parallel fiber-Purkinje cell synapses in the cerebellum embodies part of the neuronal information storage required for associative motor learning. Transgenic mice in which LTD is blocked by Purkinje cell-specific inhibition of protein kinase C (PKC) (L7-PKCI mutants) do indeed show impaired adaptation of their vestibulo-ocular reflex, whereas the dynamics of their eye movement performance are unaffected. However, because L7-PKCI mutants have a persistent multiple climbing fiber innervation at least until 35 d of age and because the baseline discharge of the Purkinje cells in the L7-PKCI mutants is unknown, factors other than a blockage of LTD induction itself may underlie their impaired motor learning. We therefore investigated the spontaneous discharge of Purkinje cells in alert adult L7-PKCI mice as well as their multiple climbing fiber innervation beyond the age of 3 months. We found that the simple spike and complex spike-firing properties (such as mean firing rate, interspike interval, and spike count variability), oscillations, and climbing fiber pause in the L7-PKCI mutants were indistinguishable from those in their wild-type littermates. In addition, we found that multiple climbing fiber innervation does not occur in cerebellar slices obtained from 3- to 6-month-old mutants. These data indicate (1) that neither PKC inhibition nor the subsequent blockage of LTD induction disturbs the spontaneous discharge of Purkinje cells in alert mice, (2) that Purkinje cell-specific inhibition of PKC detains rather than prevents the developmental conversion from multiple to mono-innervation of Purkinje cells by climbing fibers, and (3) that as a consequence the impaired motor learning as observed in older adult L7-PKCI mutants cannot be attributable either to a disturbance in the baseline simple spike and complex spike activities of their Purkinje cells or to a persistent multiple climbing fiber innervation. We conclude that cerebellar LTD is probably one of the major mechanisms underlying motor learning, but that deficits in LTD induction and motor learning as observed in the L7-PKCI mutants may only be reflected in differences of the Purkinje cell signals during and/or directly after training.