Hirata Riki, Matsumoto Machiko, Judo Chika, Yamaguchi Taku, Izumi Takeshi, Yoshioka Mitsuhiro, Togashi Hiroko
Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Synapse. 2009 Jul;63(7):549-56. doi: 10.1002/syn.20631.
Hippocampal long-term potentiation (LTP) is suppressed not only by stress paradigms but also by low frequency stimulation (LFS) prior to LTP-inducing high frequency stimulation (HFS; tetanus), termed metaplasticity. These synaptic responses are dependent on N-methyl-D-aspartate receptors, leading to speculations about the possible relationship between metaplasticity and stress-induced LTP impairment. However, the functional significance of metaplasticity has been unclear. The present study elucidated the electrophysiological and neurochemical profiles of metaplasticity in the hippocampal CA1 field, with a focus on the synaptic response induced by the emotional stress, contextual fear conditioning (CFC). The population spike amplitude in the CA1 field was decreased during exposure to CFC, and LTP induction was suppressed after CFC in conscious rats. The synaptic response induced by CFC was mimicked by LFS, i.e., LFS impaired the synaptic transmission and subsequent LTP. Plasma corticosterone levels were increased by both CFC and LFS. Extracellular levels of gamma-aminobutyric acid (GABA), but not glutamate, in the hippocampus increased during exposure to CFC or LFS. Furthermore, electrical stimulation of the medial prefrontal cortex (mPFC), which caused decreases in freezing behavior during exposure to CFC, counteracted the LTP impairment induced by LFS. These findings suggest that metaplasticity in the rat hippocampal CA1 field is related to the neural basis of stress experience-dependent fear memory, and that hippocampal synaptic response associated stress-related processes is under mPFC regulation.
海马体长期增强效应（LTP）不仅会被应激范式所抑制，还会在诱导LTP的高频刺激（HFS；强直刺激）之前被低频刺激（LFS）所抑制，这被称为元可塑性。这些突触反应依赖于N-甲基-D-天冬氨酸受体，从而引发了关于元可塑性与应激诱导的LTP损伤之间可能关系的推测。然而，元可塑性的功能意义尚不清楚。本研究阐明了海马体CA1区元可塑性的电生理和神经化学特征，重点关注由情绪应激即情境恐惧条件反射（CFC）诱导的突触反应。在暴露于CFC期间，CA1区群体峰电位幅度降低，并且在清醒大鼠中，CFC后LTP诱导受到抑制。CFC诱导的突触反应可被LFS模拟，即LFS损害突触传递及随后的LTP。CFC和LFS均使血浆皮质酮水平升高。在暴露于CFC或LFS期间，海马体中γ-氨基丁酸（GABA）而非谷氨酸的细胞外水平升高。此外，对内侧前额叶皮质（mPFC）进行电刺激，这会导致在暴露于CFC期间冻结行为减少，抵消了LFS诱导的LTP损伤。这些发现表明，大鼠海马体CA1区的元可塑性与应激经历依赖性恐惧记忆的神经基础有关，并且与应激相关过程相关的海马体突触反应受mPFC调节。
