Signaling cascade regulating long-term potentiation of GABAA receptor responsiveness in cerebellar Purkinje neurons
Signaling cascade regulating long-term potentiation of GABAA receptor responsiveness in cerebellar Purkinje neurons
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DOI：
10.1523/jneurosci.22-10-03969.2002
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发表时间：
2002-05-15
影响因子：
5.3
通讯作者：
Hirano, T
中科院分区：
文献类型：
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作者：
Kawaguchi, S;Hirano, T
突触可塑性是学习和记忆的细胞基础，已在兴奋性突触中进行了广泛的研究。虽然在抑制性突触中也有突触可塑性的报道，但其分子机制仍不清楚。本研究旨在阐明小脑中抑制性突触可塑性诱导的信号级联反应，即GABA（A）受体（GABA（A）R）反应性的长期增强，是由浦肯野神经元（PN）与抑制性中间神经元（星状或篮状神经元）形成的突触后去极化引起的。以前，我们表明，RP是抑制去极化过程中通过激活突触后GABA（B）受体（GABA（B）R）的同突触激活。GABA（B）R的激活通过G（i）/G（o）-蛋白降低cAMP依赖性蛋白激酶（PKA）活性。在这里，我们研究了PKA活性影响RP诱导的分子途径，我们证实，抑制Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）或PKA抑制RP。我们还发现，蛋白磷酸酶1（PP-1）或钙调神经磷酸酶（PP-2B）的抑制受损的RP诱导的抑制。抑制PP-1或钙调磷酸酶废除RP损伤PKA抑制，但不是由CaMKII抑制。DARPP-32是PKA和钙调磷酸酶的底物，当被PKA磷酸化时抑制PP-1，反义寡核苷酸介导的DARPP-32敲低抑制RP。此外，GABA（B）R的激活通过PKA抑制和PP-1活性抑制CaMK II的激活。这些结果表明，在PN中伴随PKA抑制的钙调磷酸酶激活引起DARPP-32的去磷酸化，其从抑制中释放PP-1。PP-1反过来抑制CaMKII活性，然后直接参与RP诱导。
Synaptic plasticity, a cellular basis of learning and memory, has been studied extensively at excitatory synapses. Although synaptic plasticity has also been reported at inhibitory synapses, the molecular mechanism remains elusive. Here we attempted to clarify the overall signaling cascades regulating the induction of inhibitory synaptic plasticity in the cerebellum.Rebound potentiation (RP), a long-lasting increase in GABA(A) receptor (GABA(A)R) responsiveness, is induced by postsynaptic depolarization of a Purkinje neuron (PN) at synapses formed with inhibitory interneurons (stellate or basket neurons). Previously, we showed that RP is suppressed by homosynaptic activation during depolarization through activation of the postsynaptic GABA(B) receptor (GABA(B)R). Activation of GABA(B)R reduces cAMP-dependent protein kinase (PKA) activity via the G(i)/G(o)-protein. Here we examined the molecular pathway through which PKA activity affects RP induction.We confirmed that inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) or PKA suppresses RP. We also found that inhibition of protein phosphatase 1 (PP-1) or calcineurin (PP-2B) impaired suppression of RP induction. Inhibition of either PP-1 or calcineurin abolished RP impairment by PKA inhibition, but not that by CaMKII inhibition. Antisense oligonucleotide-mediated knock down of DARPP-32, which is a substrate of PKA and calcineurin and inhibits PP-1 when phosphorylated by PKA, suppressed RP. Furthermore, activation of GABA(B)R inhibited CaMKII activation through PKA inhibition and PP-1 activity. These results suggest that calcineurin activation accompanied by PKA inhibition in a PN causes dephosphorylation of DARPP-32, which releases PP-1 from inhibition. PP-1 in turn inhibits CaMKII activity, which is then directly involved in the RP induction.