Taylor J R, Birnbaum S, Ubriani R, Arnsten A F
Department of Psychiatry and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8001, USA.
J Neurosci. 1999 Sep 15;19(18):RC23. doi: 10.1523/JNEUROSCI.19-18-j0001.1999.
Activation of the adenylyl cyclase-cAMP-protein kinase A (PKA) intracellular signaling cascade is necessary for long-term memory consolidation in brain regions such as the hippocampus. However, the role of the PKA cascade in the working memory functions of the prefrontal cortex (PFC) is unknown. The present study examined the effects of manipulating PKA activity in the PFC using the cAMP stereoisomers Sp-cAMPS and Rp-cAMPS, which activate and inhibit PKA, respectively. Animals received bilateral infusions of Sp-cAMPS and/or Rp-cAMPS into the PFC immediately before testing on the delayed alternation task, a test of spatial working memory that depends on the integrity of the PFC. Low doses of Sp-cAMPS (0.21, 2. 1, or 21 nmol/0.5 microl) produced a marked, dose-dependent impairment in working memory performance. The impairment produced by infusion of Sp-cAMPS (21 nmol/0.5 microl) was fully reversed by co-infusion of Rp-cAMPS (21 nmol/0.5 microl), consistent with actions on PKA. Rp-cAMPS (21 or 42 nmol/0.5 microl) by itself had no effect on performance. These results indicate that activation of the PKA intracellular signaling cascade in the PFC impairs working memory performance. The current findings contrast with studies of long-term memory consolidation, in which inhibition of PKA with agents such as Rp-cAMPS impaired memory consolidation (Bernabeu et al., 1997; Bourtchouladze et al., 1998), whereas enhancement of the PKA pathway improved memory (Bernabeu et al., 1997; Barad et al., 1998). These results demonstrate that discrete cognitive processes subserved by different cortical regions are mediated by distinct intracellular mechanisms.
腺苷酸环化酶 - cAMP - 蛋白激酶A（PKA）细胞内信号级联的激活对于海马体等脑区的长期记忆巩固是必要的。然而，PKA级联在前额叶皮质（PFC）工作记忆功能中的作用尚不清楚。本研究使用cAMP立体异构体Sp - cAMPS和Rp - cAMPS分别激活和抑制PKA，研究了操纵PFC中PKA活性的效果。在对延迟交替任务进行测试之前，动物立即接受双侧向PFC注入Sp - cAMPS和/或Rp - cAMPS，延迟交替任务是一种依赖于PFC完整性的空间工作记忆测试。低剂量的Sp - cAMPS（0.21、2.1或21 nmol / 0.5微升）对工作记忆表现产生显著的、剂量依赖性损害。注入Sp - cAMPS（21 nmol / 0.5微升）所产生的损害可通过共注入Rp - cAMPS（21 nmol / 0.5微升）完全逆转，这与对PKA的作用一致。单独使用Rp - cAMPS（21或42 nmol / 0.5微升）对表现没有影响。这些结果表明，PFC中PKA细胞内信号级联的激活会损害工作记忆表现。目前的研究结果与长期记忆巩固的研究形成对比，在长期记忆巩固研究中，使用诸如Rp - cAMPS等药物抑制PKA会损害记忆巩固（贝纳贝乌等人，1997年；布尔乔拉德泽等人，1998年），而增强PKA途径则改善了记忆（贝纳贝乌等人，1997年；巴拉德等人，1998年）。这些结果表明，不同皮质区域所支持的离散认知过程由不同的细胞内机制介导。
