Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome
Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome
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DOI：
10.1523/jneurosci.1766-04.2004
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发表时间：
2004-09-15
影响因子：
5.3
通讯作者：
Mobley, WC
中科院分区：
文献类型：
--
作者：
Kleschevnikov, AM;Belichenko, PV;Mobley, WC
尽管许多遗传疾病的特征是发育过程中的认知障碍，但对异常的神经生物学基础知之甚少。唐氏综合症（DS）是一种由21号染色体（21三体）的三个拷贝引起的疾病，其特征是海马功能障碍导致的学习和记忆障碍。我们在Ts65Dn小鼠（DS的遗传模型）中探索了这些异常的细胞基础。尽管齿状回的基础突触传递正常，但由于NMDA受体激活减少，长期增强（LTP）功能严重受损。在GABA(a)受体拮抗剂picrotoxin抑制后，NMDA受体介导的电流被正常化，LTP的诱导恢复。一些证据表明，Ts65Dn齿状回的抑制被增强，至少部分是由于突触前异常。这些发现提出了一种可能性，即类似的变化导致了退行性椎体滑移患者的学习和记忆异常，或许也导致了其他认知功能障碍患者的学习和记忆异常。
Althoughmanygenetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 ( trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.