The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus
The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus
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DOI：
10.1523/jneurosci.2931-04.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Muller, D
中科院分区：
文献类型：
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作者：
Boda, B;Alberi, S;Muller, D
编码PAK3（p21激活激酶3）的基因突变与X连锁的非综合征型精神发育迟滞（MRX）相关，其中唯一显著的临床特征是认知缺陷。PAK3突变产生智力障碍的机制尚不清楚，尽管已提出参与调节突触网络形成或可塑性的机制。在这里，我们表明，使用瞬时转染方法，反义和小干扰RNA介导的PAK3抑制或在大鼠海马器官型切片培养中携带人MRX30突变的显性负性PAK3的表达导致异常伸长的树突棘和丝状伪足样突起的形成以及成熟棘突触的减少。对携带MRX30突变的PAK3表达诱导的变化的超微结构分析表明，许多细长的棘不能表达突触后密度或接触突触前末梢。这些缺陷与自发活动减少、AMPA型谷氨酸受体表达改变和长时程增强缺陷有关。总之，这些数据确定PAK3作为海马中突触形成和可塑性的关键调节因子，并支持这些缺陷可能导致这种形式的智力迟钝的认知缺陷的解释。
Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation.