Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice
Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice
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DOI：
10.1007/s12035-018-1365-5
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发表时间：
2019-06-01
影响因子：
5.1
通讯作者：
Hoelter, Sabine M.
中科院分区：
文献类型：
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作者：
Heermann, Tamara;Garrett, Lillian;Hoelter, Sabine M.
B2-晶状体蛋白（B2-crystallin，BBB 2）是透镜中的一种结构蛋白，属于β-超家族，其基因突变可引起白内障。HIBBB2也在非晶状体组织如成年小鼠脑中表达，并且与神经精神障碍如精神分裂症相关。尽管如此，这种关联的稳健性以及PDBB2如何有助于疾病相关表型尚不清楚。为了进一步澄清这一问题，我们对Crybb2基因C末端等位基因突变系列小鼠的行为和神经组织学改变进行了全面分析。这三个B2突变株Crybb2（O377）、Crybb2（Philly）和Crybb2（Aey2）的行为表型包括评估旷场中的探索活动和焦虑相关行为、通过声惊吓反射的前脉冲抑制（PPI）测量的感觉运动门控、通过社会辨别测量的认知表现和Y迷宫中的自发交替。在每个突变株系中，我们还定量了在所选的表达GABBB2的脑区域中的小清蛋白阳性（PV+）GABA能中间神经元的数量。虽然个体行为和受影响的脑区存在等位基因特异性差异，但所有三种突变株系均表现出PPI的一致改变，这导致丘脑网状核（TRN）中PV+细胞数量的改变。PPI变化的方向反映了TRN PV+细胞数量的方向，从而表明TRN PV+细胞数量在调节PPI中的作用。此外，由于PPI和PV+细胞数量的改变都是精神分裂症相关的内表型，我们的结果暗示突变的Crybb2在这种神经精神疾病的发展中。
As part of the -superfamily, B2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three B2-mutant lines Crybb2(O377), Crybb2(Philly), and Crybb2(Aey2) included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.