Neurofibromin regulation of ERK signaling modulates GABA release and learning.
Neurofibromin regulation of ERK signaling modulates GABA release and learning.
复制标题
ERK信号传导的神经纤维素调节调节GABA释放和学习。
DOI：
10.1016/j.cell.2008.09.060
复制
发表时间：
2008-10-31
期刊：
影响因子：
64.5
通讯作者：
Silva AJ
中科院分区：
文献类型：
--
作者：
Cui Y;Costa RM;Murphy GG;Elgersma Y;Zhu Y;Gutmann DH;Parada LF;Mody I;Silva AJ
我们发现了ERK信号在GABA释放，长时程增强（LTP）和学习中的新作用，并表明这种机制的破坏导致了I型神经纤维瘤病（NF 1）小鼠模型的学习缺陷，这是学习障碍的常见遗传原因。遗传学、药理学、电生理学和行为学数据表明，神经纤维蛋白调节ERK/突触蛋白I依赖的GABA释放，这反过来又调节海马LTP和学习。Nf 1杂合无效突变导致ERK和突触蛋白I磷酸化增强，增加了海马中突触前GABA的释放，这可通过ERK信号转导下调逆转。重要的是，与Nf 1突变相关的学习缺陷被阈下剂量的GABAA拮抗剂挽救。因此，Cre缺失的Nf 1基因表明，只有那些涉及抑制性神经元的缺失引起海马抑制，LTP和学习异常。重要的是，我们的研究结果还揭示了学习引发的GABA释放的持续增加，表明这里揭示的机制对学习和记忆具有普遍的重要性。
We uncovered a new role for ERK signaling in GABA release, long-term potentiation (LTP) and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for Neurofibromatosis type I (NF1), a common genetic cause for learning disabilities. Genetic, pharmacological, electrophysiological and behavioral data demonstrate that neurofibromin modulates ERK/synapsin I dependent GABA release, which in turn modulate hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased pre-synaptic GABA release in the hippocampus which was reversed by pharmacologically down-regulating ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a sub-threshold dose of a GABAA antagonist. Accordingly, Cre-deletions of the Nf1 gene showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning and memory.
登录
查看更多内容
DOI：
10.1016/s0163-1047(05)80068-8
发表时间：
1994-03-01
期刊：
BEHAVIORAL AND NEURAL BIOLOGY
影响因子：
--
作者：
INTROINICOLLISON, IB;CASTELLANO, C;MCGAUGH, JL
通讯作者：
MCGAUGH, JL
影响因子：
4.7
作者：
Atack, John R.;Bayley, Peter J.;Dawson, Gerard R.
通讯作者：
Dawson, Gerard R.
影响因子：
2.7
作者：
Lindner, MD
通讯作者：
Lindner, MD
影响因子：
56.9
作者：
KIM, JJ;FANSELOW, MS
通讯作者：
FANSELOW, MS
影响因子：
5.3
作者：
Kleschevnikov, AM;Belichenko, PV;Mobley, WC
通讯作者：
Mobley, WC