Fujihara Kazuyuki, Sato Takumi, Higeta Kazuya, Miyasaka Yoshiki, Mashimo Tomoji, Yanagawa Yuchio
Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Department of Psychiatry and Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Front Pharmacol. 2021 Mar 30;12:646088. doi: 10.3389/fphar.2021.646088. eCollection 2021.
Glutamate decarboxylase 67-kDa isoform (GAD67), which is encoded by the gene, is one of the key enzymes that produce GABA. The reduced expression of GAD67 has been linked to the pathophysiology of schizophrenia. Additionally, the excitatory glutamatergic system plays an important role in the development of this disorder. Animal model studies have revealed that chronic blockade of NMDA-type glutamate receptors can cause GABAergic dysfunction and long-lasting behavioral abnormalities. Based on these findings, we speculated that haplodeficiency combined with chronic NMDA receptor blockade would lead to larger behavioral consequences relevant to schizophrenia in a rat model. In this study, we administered an NMDAR antagonist, MK-801 (0.2 mg/kg), to CRISPR/Cas9-generated rats during adolescence to test this hypothesis. The MK-801 treated rats showed a shorter duration in each rearing episode in the open field test than the saline-treated rats. In contrast, immobility in the forced swim test was increased and fear extinction was impaired in rats irrespective of MK-801 treatment. Interestingly, the time spent in the center region of the elevated plus-maze was significantly affected only in the saline-treated rats. Additionally, the MK-801-induced impairment of the social novelty preference was not observed in rats. These results suggest that the synergistic and additive effects of haplodeficiency and NMDA receptor blockade during adolescence on the pathogenesis of schizophrenia may be more limited than expected. Findings from this study also imply that these two factors mainly affect negative or affective symptoms, rather than positive symptoms.
由该基因编码的67 kDa亚型谷氨酸脱羧酶（GAD67）是产生γ-氨基丁酸（GABA）的关键酶之一。GAD67表达降低与精神分裂症的病理生理学有关。此外，兴奋性谷氨酸能系统在该疾病的发展中起重要作用。动物模型研究表明，慢性阻断NMDA型谷氨酸受体可导致GABA能功能障碍和长期行为异常。基于这些发现，我们推测单倍体不足与慢性NMDA受体阻断相结合会在大鼠模型中导致与精神分裂症相关的更大行为后果。在本研究中，我们在青春期给CRISPR/Cas9基因编辑产生的单倍体不足大鼠注射NMDA受体拮抗剂MK-801（0.2mg/kg）以验证这一假设。在旷场试验中，MK-801处理的单倍体不足大鼠每次竖毛发作的持续时间比生理盐水处理的单倍体不足大鼠短。相比之下，无论是否用MK-801处理，单倍体不足大鼠在强迫游泳试验中的不动时间均增加，恐惧消退受损。有趣的是，仅在生理盐水处理的单倍体不足大鼠中，高架十字迷宫中央区域停留的时间受到显著影响。此外，在单倍体不足大鼠中未观察到MK-801诱导的社会新奇偏好受损。这些结果表明，青春期单倍体不足和NMDA受体阻断对精神分裂症发病机制的协同和累加作用可能比预期更有限。本研究结果还表明，这两个因素主要影响阴性或情感症状，而非阳性症状。
