Nguyen P V, Duffy S N, Young J Z
Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
J Neurophysiol. 2000 Nov;84(5):2484-93. doi: 10.1152/jn.2000.84.5.2484.
Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.
转基因小鼠和基因敲除小鼠被广泛用于阐明海马突触可塑性的分子机制。然而，用于构建遗传模型的近交系小鼠品系之间的遗传和表型差异，可能会混淆从这些模型中获得的细胞神经生理学数据的解释。我们使用体外脑片刺激和记录方法，比较了四种近交系小鼠（C57BL/6J、CBA/J、DBA/2J和129/SvEms/J）海马CA1神经元的膜生物物理特性、细胞电生理特性和突触可塑性特性。由θ波模式刺激以及在不同爆发间隔下重复多脉冲100Hz刺激诱导的海马长时程增强（LTP），在BL/6J小鼠脑片的CA1区域比在CBA和DBA小鼠脑片中维持得更好。在20秒的爆发间隔下，与BL/6J脑片相比，CBA和DBA脑片中LTP的维持受损。当爆发间隔缩短至3秒时，129/SvEms脑片中LTP的诱导显著增强，但在DBA和CBA脑片中没有。这四种品系脑片之间的长时程抑制（LTD）没有显著差异。对于所检测的这四种品系，CA1锥体神经元在放电频率适应性、膜输入电阻以及电流注入引发的放电次数方面没有显著差异。在这四种品系的CA1锥体神经元中，突触诱发的谷氨酸能突触后电流没有显著差异。由于观察到的LTP缺陷类似于先前在海马cAMP依赖性蛋白激酶（PKA）活性降低的转基因小鼠中看到的缺陷，我们研究了由福斯可林（一种腺苷酸环化酶激活剂）和异丁基甲基黄嘌呤（一种磷酸二酯酶抑制剂）诱导的cAMP依赖性突触易化中可能存在的品系依赖性差异。我们发现，福斯可林/异丁基甲基黄嘌呤诱导的突触易化在DBA/2J和CBA/J脑片的CA1区域存在缺陷，但在BL/6J和129/SvEms/J脑片中没有。cAMP诱导的突触易化中的这些缺陷可能是先前报道的CBA/J和DBA/2J小鼠记忆缺陷的基础。我们得出结论，海马LTP受遗传背景和刺激方案的时间特征影响。一些近交系小鼠品系中海马突触的可塑性可能被“调整”到特定的突触活动时间模式。从更广泛的角度来看，我们的数据支持这样一种观点，即遗传背景中的品系依赖性变异是一个重要因素，它可以影响在利用转基因小鼠探索突触可塑性分子基础的研究中观察到的突触可塑性表型。
