Neuroscience Research Australia (NeuRA), Randwick, Australia; School of Psychiatry, University of New South Wales, Kensington, Australia.
Pharmacological Sciences, School of Medicine, Stony Brook University, New York, USA.
Pharmacol Biochem Behav. 2018 Jul;170:64-70. doi: 10.1016/j.pbb.2018.05.003. Epub 2018 May 8.
Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ-tetrahydrocannabinol (D-THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia. To investigate whether mice heterozygous for type III Nrg1 (i.e. knockout: type III Nrg1) are more susceptible to the behavioural effects of acute doses of D-THC, we injected male mice with either vehicle or D-THC (3 or 10 mg/kg) before testing them for locomotion, anxiety, social interaction, and sensorimotor gating. Acute D-THC led to reduced locomotion and reduced social interaction, but increased anxiety in mice. Furthermore, type III Nrg1 males displayed a robust deficit in sensorimotor gating and demonstrated reduced following during social interaction across drug conditions. However, they did not show a change in behavioural susceptibility to acute D-THC compared to controls. These results reinforce the validity of type III Nrg1 mice for schizophrenia research and suggest that loss of function of type III Nrg1 may not be responsible for the exaggerated response to acute D-THC observed in heterozygous Nrg1 TM mice. This highlights the importance of careful consideration of Nrg1 isoform type differences.
携带精神分裂症风险基因神经调节蛋白 1（NRG1）跨膜结构域突变的小鼠更容易受到Δ-四氢大麻酚（D-THC）的神经行为影响，D-THC 是大麻中的主要精神活性成分。然而，NRG1 的转录非常复杂，有超过 30 种不同的异构体，其中大多数都带有跨膜结构域，这就提出了一个问题，即哪种 NRG1 异构体可能导致这种表型。III 型 NRG1/Nrg1 是大脑中含量最丰富的异构体，大脑研究已经确定，携带精神分裂症 NRG1 风险单倍型的人类大脑中 III 型 NRG1 mRNA 水平升高。为了研究 III 型 Nrg1 杂合子（即敲除：III 型 Nrg1）的小鼠是否更容易受到急性 D-THC 剂量的行为影响，我们给雄性小鼠注射了载体或 D-THC（3 或 10mg/kg），然后测试它们的运动、焦虑、社交互动和感觉运动门控。急性 D-THC 导致运动减少和社交互动减少，但增加了小鼠的焦虑。此外，III 型 Nrg1 雄性小鼠在感觉运动门控方面表现出明显的缺陷，并且在药物条件下社交互动时的跟随行为减少。然而，与对照组相比，它们在对急性 D-THC 的行为易感性方面没有变化。这些结果加强了 III 型 Nrg1 小鼠在精神分裂症研究中的有效性，并表明 III 型 Nrg1 的功能丧失可能不是导致杂合 Nrg1 TM 小鼠对急性 D-THC 反应过度的原因。这突出了仔细考虑 NRG1 异构体类型差异的重要性。
