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Original Article Increased Glutamic Acid Decarboxylase Expression in the Hippocampus Impairs Learning and Memory in Fmr1 Knockout Mice

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Original Article Increased Glutamic Acid Decarboxylase Expression in the Hippocampus Impairs Learning and Memory in Fmr1 Knockout Mice Int J Clin Exp Med 2018;11(4):3121-3134 www.ijcem.com /ISSN:1940-5901/IJCEM0069451 Original Article Increased glutamic acid decarboxylase expression in the hippocampus impairs learning and memory in Fmr1 knockout mice Li-Jun Dai1, Yue-Ling Huang1, Wei-Wen Sun2, Bing-Fei Ye1, Sheng-Qiang Chen2 1The Laboratory Animal Center, Guangzhou Medical University, Guangzhou 510182, China; 2Institute of Neurosci- ence, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China Received March 15, 2016; Accepted February 14, 2018; Epub April 15, 2018; Published April 30, 2018 Abstract: This study compares the behavioral differences in 4- and 6-week-old mice in hippocampal expression of glutamic acid decarboxylase (GAD). Using immunoblotting and immunohistochemical staining, we compared the changed GAD expression in Fmr1 knockout mice. We detected the amino acid levels of hippocampus by high performance liquid chromatography, the data were analyzed with Multifactor Variance Analysis. Fmr1 knock out (KO) mice showed a higher expression of GAD65/67 protein in hippocampus than the Fmr1 wild type (WT) mice (P < 0.05). The six-week KO mice and WT mice exhibited a higher expression of GAD65/67 protein (in hippocampus) than their four-week counterpart (P < 0.05). KO mice showed a higher number of GAD65/67-positive neurons in hippocampus and cortex than the WT mice of the same week (P < 0.05). The six-week KO mice and WT mice contain a greater number of GAD65/GAD67-positive neurons in hippocampus than their four-week counterpart (P < 0.05). The γ-aminobutyric acid and aspartate levels in KO group were lower than WT mice, while the level of glutamate in KO was higher than WT group. Altered GAD protein levels in KO mice may play an important role in their abnormal learning and memory behavior in Fmr1 knockout mice. Keywords: Passive avoidance test, Fmr1 knockout mice, behaviour, GAD, hippocampus Introduction inhibitory imbalances and synaptic dysfunction are proposed to play a central role in a number Fragile X syndrome (FXS) is a common heredi- of pathological states, including FXS and auti- tary disease associated with mental retarda- sm spectrum disorder (ASD). FXS has varying tion. The CCG repetitive sequence amplification degrees of cognitive ability, ranging from nor- and silencing of the secondary promoter region mal to severely impaire [11-13]. FXS has a male of the methylated FMR1 (fragile x gene) cause bias, but also affects women with severe cogni- deficiency in FMR1 (fragile X mental retardation tive impairment [14, 15]. Comorbidity of autism 1) protein leading to mental retardation, behav- and FXS has been established [16, 17]. Its ioral anomalies and macro-orchidism [1-8]. The characteristics include disruptions in cognition, genetic basis of FXS involves a CGG repeat social skills, sensitivity to stimuli and circadian expansion mutation in the Fmr1 gene, which rhythms [17-22]. These conditions are modeled codes for fragile X mental retardation protein in Fmr1 knockout mice that display several (FMRP), an RNA-binding protein involved in the phenotypes of FXS, Thus, Fmr1 knockout mice trans-port and translational regulation of a provide an important animal model to study wide array of cellular and synaptic proteins. characteristics of FXS. Fmr1 KO mice, originally Fragile X syndrome (FXS) affects 1 in 4000- created by the Dutch-Belgian Consortium are 6000 people worldwide [9, 10], FXS patients frequently used as models of FXS. Fmr1 (fragile are characterized by anxiety, sensory hypersen- X mental retardation 1) knockout mouse lacks sitivity, and elevated incidence of epilepsy, con- normal FMR1 protein, manifests abnormal sistent with dysfunction and imbalance in excit- behavior, mental retardation, memory impair- atory and inhibitory neurotransmission in the ment and macro-orchidism [1-8], and is linked amygdala, cortex, and hippocampus. Excitatory- to autism at the molecular level [23-25]. The GAD and avoidance behaviour of Fmr1 KO mice CGG expansion size is correlated with spatial Neuroscience, Second Affiliated Hospital of performance in FXS males [26]. In addition, Guangzhou Medical College, China, from Janu- Fragile X Mental Retardation 1 (FMR1) expres- ary to December 2010. Animals were bred and sion is high in the hippocampus [27]. Hippo- reproduced by Guangzhou Medical College campus has been shown to be necessary for Laboratory Animal Center. The operation and the formation of spatial memory in humans and breeding procedures of animals in this study rodents. The “mGluR Theory of Fragile X” [23] conformed to animal breeding management postulates that lack of FMRP leads to defective standards of Guangdong Province and Guang- protein translation downstream of group I zhou Medical College Laboratory, and followed metabotropic glutamate receptors (mGluRs), humanitarian principles. Animals were housed leading to enhanced mGluR signaling, which in laboratory for 7 days to adapt to the environ- contributes to impaired learning and memory of ment before experiment, at room temperature FXS. Reducing group I mGluR signaling should (23 ± 2)°C, had access to food and water ad alleviate some of the symptoms of FXS [28]. libitum. Experimental processes were main- Evidence for changes in the GABAergic system tained quiet indoors. Experimental procedures in FXS has also emerged [29-34]. Jorge R [35] were performed in accordance with the Gui- investigated the role of GABA, the major inhibi- dance Suggestions for the Care and Use of tory transmitter of the brain, in the consolida- Laboratory Animals, issued by the Ministry of tion and generalization of conditioned fear and Science and Technology of the People’s in associated network activities in the hippo- Republic of China. campus. These processes are mediated by the experience-dependent regulation of GABA FVB Fmr1 KO mouse and wild counterpart WT synthesis through the glutamic acid decarbox- mouse were kindly provided by Professor BA ylase [36], which account for more than 99% of Oostra from Erasmus University Rotterdam, the GABA synthesis in the brain. Netherland Cell Biology and Genetics Research Center. Select FMR1 KO homozygote (-/-) and The Morris water maze (MWM) is widely used WT homozygote (+/+) FVB inbred line mice, to investigate hippocampus-dependent spatial were grouped according to age (4 or 6 weeks) in learning and memory in rodents. Mouse pas- four groups of 15 each. sive avoiding experiment also is one of the commonly used methods to evaluate memory Genotype identification of experimental ani- and learning ability of central nervous system mals of mouse. Previous studies of Fmr1 KO mice in learning and memory have not consistently Fmr1 gene of KO mice was inserted with neo- reported deficits [37, 38]. In this study, we mycin segment. All the experimental mice were observed 4- and 6-week-old Fmr1 knockout genotyped before use to ensure that the strains mice using passive avoidance and tested were purebred [3]. Design primer 5’-GTGGTTA- changes of Fmr1 knockout mouse hippocam- GCTAAAGTGAGGATGAT-3’ and 5’-CAGGTTTGTT- pus GAD expression. We discussed the rela- GGGATTAACAGATC-3’ in order to detect WT tionship between learning and memory of Fmr1 mice. Design primer 5’-AGTCATGCTATGGATAT- knockout mice and changes in hippocampus CAG-3’ and 5’-TGGGCTCTATGGCTTCTGA-3’ de- GAD expression. We used high performance liq- tect KO mice. We can identify the genotyping of uid chromatography (HPLC) to quantify the hip- experimental animal by polymerase chain reac- pocampal tissue concentrations of aspartate tion (PCR) and electrophoresis Genotype identi- and glutamate, GABA and taurine, discussed fication of experimental animals. the pathogenesis of fragile X syndrome, and discuss the evidence in brain development and Step-through test aging research. BA-200 mice step-through instrument was Materials and methods used to test the step-through behaviors of mice (Thaimeng Science and Technology Company, Laboratory animals Chengdu, Sichuan, China). The mice in the bright chamber headed back toward the door This study, a randomized, controlled animal before training. After adapting to the environ- experiment was performed at the Institute of ment for 3 minutes, power was connected to 3122 Int J Clin Exp Med 2018;11(4):3121-3134 GAD and avoidance behaviour of Fmr1 KO mice copper grid in the black chamber at a voltage Neurotechnologies, Baltimore, MD) [4, 5], fol- 36v. The mouse in the dark chamber received lowing the manufacturer’s guidelines. Briefly, an electric shock. The normal reaction involves freshly removed brains were immersed in a mouse heading back to bright chamber. Copper proprietary impregnated solution and stored grid was switched on for 5 minutes. The mouse at room temperature for 2 weeks in the dark. learning and memory tests were administered Next, the brains were transferred to a second after 24 hours. The first entry of the mouse into impregnation solution and incubated for 48 the dark chamber was defined as step-through hours at 4°C. Finally, the tissues were shipp- latency. The number of mice entering the dark- ed to FD Neurotechnologies, where they were room within 5 minutes was defined as step- sectioned to 120-mm-thick, slices, stained and through error count. If the mice failed to enter mounted on gelatin-coated slides. The slides the darkroom in 5 minutes, latency was record- were returned to UCSF for microscopic ana- ed as 300 seconds. lyses. Step-down test Dendritic spine density and spine morphology A DT-200 mice step-down instrument was used Spine analyses were conducted blinded to to test the step-down behaviors of mice the experimental conditions on coded Golgi (Thaimeng Science and Technology Company, impregnated brain sections containing the dor- Chengdu, Sichuan, China). After setting the sal hippocampus. Spines were examined on period to 5 minutes and voltage 32 V, the mice dendrites of DG granule neurons as well as were placed in each reaction tank platform to apical (stratum radiatum) and basal (stratum test for short memory. After covering the trans- oriens) dendrites of CA1 pyramidal neurons.
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