Roles of neuropeptide PACAP in regulating psychomotor functions

为了探讨内源性PACAP在高级脑/心理过程中的生理作用，对本实验室新培育的PACAP基因敲除小鼠(PACAP-L-)进行了行为学和电生理分析，得到以下结果：1.PACAP-L-小鼠表现出明显的运动活动增强和爆发性跳跃行为。抗精神病药物氟哌啶醇和选择性5-羟色胺再摄取抑制剂(SSRI)可改善这些异常行为。在旷野、高架迷宫、出现和新物体测试中，PACAP-L小鼠的探索相关行为增加，焦虑相关行为减少。PACAP-L-小鼠在4周龄时表现出正常的脉冲前抑制，但在6周龄后出现脉冲前抑制。这种降低的PPI可以被精神刺激剂改善，但不受氟哌啶醇的影响。在PACAP-L-小鼠，海马区突触强度的长时程增强(LTP)的诱导被降低。此外，PACAP杂合突变小鼠和PACAP(PAC1)受体外显子2靶向的小鼠在LTP中显示出中等程度的缺陷，这表明PACAP基因存在基因剂量效应。行为学研究表明，PACAP-L小鼠在几种行为范式中都存在记忆保持障碍。综上所述，本研究提出了PACAP能神经元在调节精神运动行为中的作用，并认为PACAP-L小鼠的表型部分类似于人类精神障碍的表型。本研究还提供了对PACAP在高级大脑功能中的作用的洞察。

To investigate the physiological roles of endogenous PACAP in higher-order brain/psychological processes, behavioral and electrophysiological analyses were carried out in PACAP gene knockout (PACAP-l-) mice which was recently generated in this laboratory, and the following results were obtained:1. PACAP-l- mice displayed markedly increased locomotor activity and explosive jumping behavior. These aberrant behaviors were ameliorated by the antipsychotic drug haloperidol and selective serotonin reuptake inhibitor (SSRI).2. Increased exploratory-related and reduced anxiety-related behavior in PACAP-l- mice was demonstrated by zone monitoring in the open field, on the elevated plus maze, and by the emergence and novel object tests.3. PACAP-l- mice exhibited normal prepulse inhibition (PPI) of the acoustic startle response at 4 weeks of age; however, they suffer impairment of PPI after 6 weeks of age.4. This reduced PPI was ameliorated by the psychostimulant, but unaffected by haloperidol.5. In PACAP-l- mice, the induction of long-term potentiation (LTP) of hippocampal synaptic strength was reduced. In addition, PACAP heterozygous mutant mice and PACAP (PAC1) receptor exon 2-targeted mice showed a moderate defect in LTP, suggesting a gene-dosage effect for the PACAP gene.6. The behavioral study revealed impaired memory retention of PACAP-l- mice in several behavioral paradigms.In conclusion, the present study proposes a role of PACAP-ergic neurons in regulating psychomotor behaviors and suggests that the phenotype of PACAP-l- mice in part resembles those in human psychiatric disorders. The present study also provides an insight into the role of PACAP in higher brain functions.