臺灣博碩士論文加值系統

自閉症類群障礙 (Autism Spectrum Disorder，ASD) 是一種神經發展異常之精神疾病。依據美國精神疾病診斷準則手冊第五版 (DSM-5)，自閉症類群障礙主要的臨床症狀為社交溝通、社會互動障礙，以及侷限的興趣與重複行為。根據世界衛生組織的統計，全球患有自閉症類群障礙的人數約占全球總人口的1~2%。而在台灣自閉症類群障礙患者的人數逐年上升。目前尚未出現有效的治癒方法，因此關於自閉症類群障礙的藥物開發及研究是迫切需要的。許多因素會造成自閉症類群障礙，其中遺傳因子扮演著重要的部分。先前的遺傳學研究指出T 型鈣離子通道基因CACNA1H 的突變與自閉症類群障礙有相當的關連性。突變基因會造成鈣離子通道的活性降低，減少鈣離子流入神經元，進而影響神經元的正常活化與功能。然而更進一步的分子機制至今尚未釐清。由於許多研究發現藉由藥物增強中樞神經系統中由γ-氨基丁酸所調控的抑制性神經傳導，可以反轉自閉症類群障礙模式小鼠的異常社交行為，已知大腦中興奮性與抑制性神經傳導不平衡之現象可能是造成自閉症類群障礙的原因，促進中樞神經系統中由γ-氨基丁酸所調控的抑制性神經傳導可能矯正此不平衡現象而對自閉症類群障礙之異常社交行為有療效。因此，實驗室先前利用T 型鈣離子通道基因Cacna1h基因剔除小鼠進行自閉症類群障礙的研究，行為測試的結果顯示Cacna1h基因剔除小鼠在新奇社交上出現異常，然而給予γ-氨基丁酸A受體之異位性活化劑「氯硝西泮」後，基因剔除小鼠的異常行為即可回復正常水平。因此，我們提出假說認為Cacna1h基因剔除小鼠的大腦中由γ-氨基丁酸所調控的抑制性神經傳導受損導致社交行為異常。透過本篇論文研究結果發現Cacna1h基因剔除小鼠的在前額葉中負責產生γ-氨基丁酸的穀氨酸脫羧酶 1 基因(Glutamate decarboxylase 1, Gad1)為低度表現，同時在免疫組織螢光染色的實驗中發現γ-氨基丁酸的免疫螢光強度在Cacna1h基因剔除小鼠的前額葉與海馬迴也有低度表現的趨勢。此外我也發現在Cacna1h基因剔除小鼠的前額葉與海馬迴內methyl CpG binding protein 2 (MeCP2)蛋白有高度表現。從先前研究指出自閉症類群障礙患者的前額葉中，表觀遺傳之抑制因子MECP2蛋白大量地與穀氨酸脫羧酶 1 基因結合而抑制穀氨酸脫羧酶 1 基因的轉錄。綜合本論文的結果顯示當失去Cacna1h基因後，可能過度表現的MeCP2蛋白使穀氨酸脫羧酶 1 基因的信使核糖核酸總量下降以及γ-氨基丁酸呈現低度表現，導致Cacna1h基因剔除小鼠出現社交行為異常。

Autism spectrum disorder (ASD) is a neuropsychiatric disorder characterized by developmental disabilities, including impaired social interaction and restrictedly repetitive patterns of behaviors or interests. The prevalence of individuals with ASD on average is between 1% - 2% worldwide. Until now, there is no cure for ASD. Therefore, it is necessary to investigate the molecular mechanism underlying ASD to identify the potential therapeutic targets. Previous studies showed that mutations in the T-type calcium channel gene CACNA1H (Cav3.2) were associated with ASD phenotypes. These mutations reduced the activity of Cav3.2 channel and subsequently affected neuronal functions. However, the underlying mechanism are still unclear. Since the excitatory/inhibitory (E/I) imbalance has been found in several ASD models, many studies have shown that drugs acting as a gamma-aminobutyric acid (GABA) agonist can rescue behavioral deficits in ASD models. Our previous study showed that the Cav3.2-/- mice exhibit ASD-like behaviors including abnormal self-grooming and impaired performance of social novelty. Interestingly, these abnormal behaviors can be reversed by injection of low dosage of clonazepam, a GABA-positive allosteric modulator. I thus hypothesize that the Cav3.2-/- mice is impaired in the GABA transmission and design experiments to investigate several GABA-related molecules to verify the hypothesis. My results revealed that mRNA expression of the Gad1, a gene encoding enzyme that can decarboxylate glutamate to produce GABA, was decreased in the frontal cortex of the Cav3.2-/- mice. In addition, the immunohistochemistry staining showed that the immunostaining density of GABA was slightly reduced in the frontal cortex and hippocampus of the Cav3.2-/- mice. Furthermore, methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor, was overexpressed in the frontal cortex and hippocampus of the Cav3.2-/- mice. Our results suggest that the loss of Cav3.2 channel lead to overexpression of MeCP2 and downregulation of the Gad1 gene, in turn, cause autistic- like behavior.

Index
致謝 I
Abstract II
Index III
Introduction 1
Autism Spectrum Disorder 1
Voltage-dependent Calcium Channels and ASD 4
The Cav3.2 T-type Calcium Channel 7
GABA transmission and Excitatory/Inhibitory Imbalance in ASD 8
The GABA Synthesis and GABAA receptor system 8
Aim 13
Materials and Methods 14
Animals and Genotyping 14
Total RNA Extraction 14
Reverse Transcription (RT) 15
qPCR (quantitative Real-Time Polymerase Chain Reaction) 16
Western Blot Analysis 17
Immunohistochemistry by Fluorescent Staining (IHC-F) 21
Statistics 23
Results 24
Discussion 28
Figures 36
Table 54
References 55

Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet, 23(2), 185-188. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10508514. doi:10.1038/13810
Atack, J. R. (2010). GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics. Curr Top Behav Neurosci, 2, 331-360. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21309116.
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., . . . Dowling, N. F. (2018). Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ, 67(6), 1-23. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29701730. doi:10.15585/mmwr.ss6706a1
Barrett, C. F., & Tsien, R. W. (2008). The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc Natl Acad Sci U S A, 105(6), 2157-2162. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18250309. doi:10.1073/pnas.0710501105
Bedford, F. K., Kittler, J. T., Muller, E., Thomas, P., Uren, J. M., Merlo, D., . . . Moss, S. J. (2001). GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1. Nat Neurosci, 4(9), 908-916. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11528422. doi:10.1038/nn0901-908
Ben-Sasson, A., Hen, L., Fluss, R., Cermak, S. A., Engel-Yeger, B., & Gal, E. (2009). A meta-analysis of sensory modulation symptoms in individuals with autism spectrum disorders. J Autism Dev Disord, 39(1), 1-11. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18512135. doi:10.1007/s10803-008-0593-3
Bernhardt, M. L., Zhang, Y., Erxleben, C. F., Padilla-Banks, E., McDonough, C. E., Miao, Y. L., . . . Williams, C. J. (2015). CaV3.2 T-type channels mediate Ca(2)(+) entry during oocyte maturation and following fertilization. J Cell Sci, 128(23), 4442-4452. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26483387. doi:10.1242/jcs.180026
Bicks, L. K., Koike, H., Akbarian, S., & Morishita, H. (2015). Prefrontal Cortex and Social Cognition in Mouse and Man. Front Psychol, 6, 1805. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26635701. doi:10.3389/fpsyg.2015.01805
Cantor, R. M., Kono, N., Duvall, J. A., Alvarez-Retuerto, A., Stone, J. L., Alarcon, M., . . . Geschwind, D. H. (2005). Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet, 76(6), 1050-1056. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15877280. doi:10.1086/430278
Catterall, W. A. (2011). Voltage-gated calcium channels. Cold Spring Harb Perspect Biol, 3(8), a003947. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21746798. doi:10.1101/cshperspect.a003947
Catterall, W. A., Perez-Reyes, E., Snutch, T. P., & Striessnig, J. (2005). International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev, 57(4), 411-425. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16382099. doi:10.1124/pr.57.4.5
Cellot, G., & Cherubini, E. (2014). GABAergic signaling as therapeutic target for autism spectrum disorders. Front Pediatr, 2, 70. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25072038. doi:10.3389/fped.2014.00070
Chao, H. T., & Zoghbi, H. Y. (2009). The yin and yang of MeCP2 phosphorylation. Proc Natl Acad Sci U S A, 106(12), 4577-4578. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19293386. doi:10.1073/pnas.0901518106
Charych, E. I., Yu, W., Miralles, C. P., Serwanski, D. R., Li, X., Rubio, M., & De Blas, A. L. (2004). The brefeldin A-inhibited GDP/GTP exchange factor 2, a protein involved in vesicular trafficking, interacts with the beta subunits of the GABA receptors. J Neurochem, 90(1), 173-189. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15198677. doi:10.1111/j.1471-4159.2004.02481.x
Chen, C. C., Lamping, K. G., Nuno, D. W., Barresi, R., Prouty, S. J., Lavoie, J. L., . . . Campbell, K. P. (2003). Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science, 302(5649), 1416-1418. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14631046. doi:10.1126/science.1089268
Chen, C. C., Shen, J. W., Chung, N. C., Min, M. Y., Cheng, S. J., & Liu, I. Y. (2012). Retrieval of context-associated memory is dependent on the Ca(v)3.2 T-type calcium channel. PLoS One, 7(1), e29384. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22235292. doi:10.1371/journal.pone.0029384
Chen, Y., Dong, E., & Grayson, D. R. (2011). Analysis of the GAD1 promoter: trans-acting factors and DNA methylation converge on the 5' untranslated region. Neuropharmacology, 60(7-8), 1075-1087. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20869372. doi:10.1016/j.neuropharm.2010.09.017
Chien, I. C., Lin, C. H., Chou, Y. J., & Chou, P. (2011). Prevalence and incidence of autism spectrum disorders among national health insurance enrollees in Taiwan from 1996 to 2005. J Child Neurol, 26(7), 830-834. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21460178. doi:10.1177/0883073810393964
Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P. (2001). De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet, 68(6), 1327-1332. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11359211. doi:10.1086/320609
Clapham, D. E. (2007). Calcium signaling. Cell, 131(6), 1047-1058. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18083096. doi:10.1016/j.cell.2007.11.028
Coghlan, S., Horder, J., Inkster, B., Mendez, M. A., Murphy, D. G., & Nutt, D. J. (2012). GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neurosci Biobehav Rev, 36(9), 2044-2055. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22841562. doi:10.1016/j.neubiorev.2012.07.005
Collinson, N., Atack, J. R., Laughton, P., Dawson, G. R., & Stephens, D. N. (2006). An inverse agonist selective for alpha5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze. Psychopharmacology (Berl), 188(4), 619-628. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16633803. doi:10.1007/s00213-006-0361-z
Collinson, N., Kuenzi, F. M., Jarolimek, W., Maubach, K. A., Cothliff, R., Sur, C., . . . Rosahl, T. W. (2002). Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci, 22(13), 5572-5580. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12097508. doi:20026436
Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G., & Moss, S. J. (1996). Assembly and cell surface expression of heteromeric and homomeric gamma-aminobutyric acid type A receptors. J Biol Chem, 271(1), 89-96. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/8550630.
Cribbs, L. L., Lee, J. H., Yang, J., Satin, J., Zhang, Y., Daud, A., . . . Perez-Reyes, E. (1998). Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res, 83(1), 103-109. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9670923.
Daghsni, M., Rima, M., Fajloun, Z., Ronjat, M., Bruses, J. L., M'Rad, R., & De Waard, M. (2018). Autism throughout genetics: Perusal of the implication of ion channels. Brain Behav, 8(8), e00978. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29934975. doi:10.1002/brb3.978
Damaj, L., Lupien-Meilleur, A., Lortie, A., Riou, E., Ospina, L. H., Gagnon, L., . . . Rossignol, E. (2015). CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Eur J Hum Genet, 23(11), 1505-1512. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25735478. doi:10.1038/ejhg.2015.21
Dani, V. S., Chang, Q., Maffei, A., Turrigiano, G. G., Jaenisch, R., & Nelson, S. B. (2005). Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A, 102(35), 12560-12565. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16116096. doi:10.1073/pnas.0506071102
Dawson, G. R., Maubach, K. A., Collinson, N., Cobain, M., Everitt, B. J., MacLeod, A. M., . . . Atack, J. R. (2006). An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther, 316(3), 1335-1345. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16326923. doi:10.1124/jpet.105.092320
de la Cruz, F. F. (1985). Fragile X syndrome. Am J Ment Defic, 90(2), 119-123. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/3901755.
Diagnostic and statistical manual of mental disorders fifth edition (DSM‐5). (2013). Washington, DC: American Psychiatric Publisher.
Erlander, M. G., Tillakaratne, N. J., Feldblum, S., Patel, N., & Tobin, A. J. (1991). Two genes encode distinct glutamate decarboxylases. Neuron, 7(1), 91-100. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/2069816.
Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M., & Luscher, B. (1998). Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci, 1(7), 563-571. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10196563. doi:10.1038/2798
Fang, C., Deng, L., Keller, C. A., Fukata, M., Fukata, Y., Chen, G., & Luscher, B. (2006). GODZ-mediated palmitoylation of GABA(A) receptors is required for normal assembly and function of GABAergic inhibitory synapses. J Neurosci, 26(49), 12758-12768. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17151279. doi:10.1523/JNEUROSCI.4214-06.2006
Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry, 52(8), 805-810. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12372652.
Francis, A., Msall, M., Obringer, E., & Kelley, K. (2013). Children with autism spectrum disorder and epilepsy. Pediatr Ann, 42(12), 255-260. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24295159. doi:10.3928/00904481-20131122-10
Gao, R., & Penzes, P. (2015). Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med, 15(2), 146-167. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25732149.
Ge, S., Goh, E. L., Sailor, K. A., Kitabatake, Y., Ming, G. L., & Song, H. (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature, 439(7076), 589-593. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16341203. doi:10.1038/nature04404
Ge, S., Pradhan, D. A., Ming, G. L., & Song, H. (2007). GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci, 30(1), 1-8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17116335. doi:10.1016/j.tins.2006.11.001
Han, S., Tai, C., Jones, C. J., Scheuer, T., & Catterall, W. A. (2014). Enhancement of inhibitory neurotransmission by GABAA receptors having alpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron, 81(6), 1282-1289. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24656250. doi:10.1016/j.neuron.2014.01.016
Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., . . . Catterall, W. A. (2012). Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature, 489(7416), 385-390. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22914087. doi:10.1038/nature11356
Harada, M., Taki, M. M., Nose, A., Kubo, H., Mori, K., Nishitani, H., & Matsuda, T. (2011). Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 tesla instrument. J Autism Dev Disord, 41(4), 447-454. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20652388. doi:10.1007/s10803-010-1065-0
Hemara-Wahanui, A., Berjukow, S., Hope, C. I., Dearden, P. K., Wu, S. B., Wilson-Wheeler, J., . . . Maw, M. A. (2005). A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc Natl Acad Sci U S A, 102(21), 7553-7558. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15897456. doi:10.1073/pnas.0501907102
Heron, S. E., Khosravani, H., Varela, D., Bladen, C., Williams, T. C., Newman, M. R., . . . Zamponi, G. W. (2007). Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol, 62(6), 560-568. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17696120. doi:10.1002/ana.21169
Hirano, T., & Kawaguchi, S. Y. (2014). Regulation and functional roles of rebound potentiation at cerebellar stellate cell-Purkinje cell synapses. Front Cell Neurosci, 8, 42. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24600347. doi:10.3389/fncel.2014.00042
Hope, C. I., Sharp, D. M., Hemara-Wahanui, A., Sissingh, J. I., Lundon, P., Mitchell, E. A., . . . Clover, G. M. (2005). Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. Clin Exp Ophthalmol, 33(2), 129-136. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15807819. doi:10.1111/j.1442-9071.2005.00987.x
Huang, H. S., & Akbarian, S. (2007). GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS One, 2(8), e809. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17726539. doi:10.1371/journal.pone.0000809
Hudson, C. C., Hall, L., & Harkness, K. L. (2019). Prevalence of Depressive Disorders in Individuals with Autism Spectrum Disorder: a Meta-Analysis. J Abnorm Child Psychol, 47(1), 165-175. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29497980. doi:10.1007/s10802-018-0402-1
Hussman, J. P., Chung, R. H., Griswold, A. J., Jaworski, J. M., Salyakina, D., Ma, D., . . . Pericak-Vance, M. A. (2011). A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism. Mol Autism, 2(1), 1. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21247446. doi:10.1186/2040-2392-2-1
Hutsler, J. J., & Zhang, H. (2010). Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res, 1309, 83-94. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19896929. doi:10.1016/j.brainres.2009.09.120
Ito, S. (2016). GABA and glycine in the developing brain. J Physiol Sci, 66(5), 375-379. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26951057. doi:10.1007/s12576-016-0442-7
Jacob, T. C., Moss, S. J., & Jurd, R. (2008). GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci, 9(5), 331-343. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18382465. doi:10.1038/nrn2370
Jedlicka, P., Papadopoulos, T., Deller, T., Betz, H., & Schwarzacher, S. W. (2009). Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Mol Cell Neurosci, 41(1), 94-100. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19236916. doi:10.1016/j.mcn.2009.02.005
Jung, E. M., Moffat, J. J., Liu, J., Dravid, S. M., Gurumurthy, C. B., & Kim, W. Y. (2017). Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat Neurosci, 20(12), 1694-1707. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29184203. doi:10.1038/s41593-017-0013-0
Kanematsu, T., Jang, I. S., Yamaguchi, T., Nagahama, H., Yoshimura, K., Hidaka, K., . . . Nakayama, K. (2002). Role of the PLC-related, catalytically inactive protein p130 in GABA(A) receptor function. EMBO J, 21(5), 1004-1011. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11867528. doi:10.1093/emboj/21.5.1004
Keller, C. A., Yuan, X., Panzanelli, P., Martin, M. L., Alldred, M., Sassoe-Pognetto, M., & Luscher, B. (2004). The gamma2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ. J Neurosci, 24(26), 5881-5891. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15229235. doi:10.1523/JNEUROSCI.1037-04.2004
Kins, S., Betz, H., & Kirsch, J. (2000). Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Nat Neurosci, 3(1), 22-29. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10607391. doi:10.1038/71096
Kittler, J. T., Arancibia-Carcamo, I. L., & Moss, S. J. (2004). Association of GRIP1 with a GABA(A) receptor associated protein suggests a role for GRIP1 at inhibitory synapses. Biochem Pharmacol, 68(8), 1649-1654. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15451408. doi:10.1016/j.bcp.2004.07.028
Kittler, J. T., McAinsh, K., & Moss, S. J. (2002). Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission. Mol Neurobiol, 26(2-3), 251-268. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12428759. doi:10.1385/MN:26:2-3:251
Kittler, J. T., Rostaing, P., Schiavo, G., Fritschy, J. M., Olsen, R., Triller, A., & Moss, S. J. (2001). The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA(A) receptors. Mol Cell Neurosci, 18(1), 13-25. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11461150. doi:10.1006/mcne.2001.1005
Kleijnen, M. F., Shih, A. H., Zhou, P., Kumar, S., Soccio, R. E., Kedersha, N. L., . . . Howley, P. M. (2000). The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell, 6(2), 409-419. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10983987.
Kneussel, M., Brandstatter, J. H., Laube, B., Stahl, S., Muller, U., & Betz, H. (1999). Loss of postsynaptic GABA(A) receptor clustering in gephyrin-deficient mice. J Neurosci, 19(21), 9289-9297. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10531433.
LeClerc, S., & Easley, D. (2015). Pharmacological therapies for autism spectrum disorder: a review. P T, 40(6), 389-397. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26045648.
Lee, E., Lee, J., & Kim, E. (2017). Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders. Biol Psychiatry, 81(10), 838-847. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27450033. doi:10.1016/j.biopsych.2016.05.011
Leigh, J. P., & Du, J. (2015). Brief Report: Forecasting the Economic Burden of Autism in 2015 and 2025 in the United States. J Autism Dev Disord, 45(12), 4135-4139. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26183723. doi:10.1007/s10803-015-2521-7
Leil, T. A., Chen, Z. W., Chang, C. S., & Olsen, R. W. (2004). GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons. J Neurosci, 24(50), 11429-11438. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15601949. doi:10.1523/JNEUROSCI.3355-04.2004
Levi, S., Logan, S. M., Tovar, K. R., & Craig, A. M. (2004). Gephyrin is critical for glycine receptor clustering but not for the formation of functional GABAergic synapses in hippocampal neurons. J Neurosci, 24(1), 207-217. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14715953. doi:10.1523/JNEUROSCI.1661-03.2004
Li, B. M., Liu, X. R., Yi, Y. H., Deng, Y. H., Su, T., Zou, X., & Liao, W. P. (2011). Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav, 21(3), 291-295. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21620773. doi:10.1016/j.yebeh.2011.04.060
Liu, X., & Takumi, T. (2014). Genomic and genetic aspects of autism spectrum disorder. Biochem Biophys Res Commun, 452(2), 244-253. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25173933. doi:10.1016/j.bbrc.2014.08.108
Marsden, K. C., Beattie, J. B., Friedenthal, J., & Carroll, R. C. (2007). NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors. J Neurosci, 27(52), 14326-14337. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18160640. doi:10.1523/JNEUROSCI.4433-07.2007
McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J., & Crawley, J. N. (2008). Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav, 7(2), 152-163. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17559418. doi:10.1111/j.1601-183X.2007.00330.x
McKernan, R. M., Rosahl, T. W., Reynolds, D. S., Sur, C., Wafford, K. A., Atack, J. R., . . . Whiting, P. J. (2000). Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci, 3(6), 587-592. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10816315. doi:10.1038/75761
Meeting report: Autism spectrum disorders & other developmental disorders: from raising awareness to building capacity. (2013).
Ming, X., Brimacombe, M., & Wagner, G. C. (2007). Prevalence of motor impairment in autism spectrum disorders. Brain Dev, 29(9), 565-570. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17467940. doi:10.1016/j.braindev.2007.03.002
Ming, Y. L., I. Y. . (2017). Reversal of Autistic-like behavior on the Cav3.2 Knockout mice by enhancing GABAergic transmission. (Master), Tzu Chi University, Taiwan. Retrieved from https://hdl.handle.net/11296/zhsfx4
Myers, S. M., Johnson, C. P., & American Academy of Pediatrics Council on Children With, D. (2007). Management of children with autism spectrum disorders. Pediatrics, 120(5), 1162-1182. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17967921. doi:10.1542/peds.2007-2362
Nanou, E., & Catterall, W. A. (2018). Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. Neuron, 98(3), 466-481. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29723500. doi:10.1016/j.neuron.2018.03.017
Nelson, S. B., & Valakh, V. (2015). Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron, 87(4), 684-698. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26291155. doi:10.1016/j.neuron.2015.07.033
O'Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., . . . Eichler, E. E. (2011). Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet, 43(6), 585-589. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21572417. doi:10.1038/ng.835
O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., . . . Shendure, J. (2012). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science, 338(6114), 1619-1622. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23160955. doi:10.1126/science.1227764
O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., . . . Eichler, E. E. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485(7397), 246-250. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22495309. doi:10.1038/nature10989
Oh, D. H., Oh, D., Son, H., Webster, M. J., Weickert, C. S., & Kim, S. H. (2014). An association between the reduced levels of SLC1A2 and GAD1 in the dorsolateral prefrontal cortex in major depressive disorder: possible involvement of an attenuated RAF/MEK/ERK signaling pathway. J Neural Transm (Vienna), 121(7), 783-792. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24652383. doi:10.1007/s00702-014-1189-z
Olmos-Serrano, J. L., Paluszkiewicz, S. M., Martin, B. S., Kaufmann, W. E., Corbin, J. G., & Huntsman, M. M. (2010). Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci, 30(29), 9929-9938. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20660275. doi:10.1523/JNEUROSCI.1714-10.2010
Ospina, M. B., Krebs Seida, J., Clark, B., Karkhaneh, M., Hartling, L., Tjosvold, L., . . . Smith, V. (2008). Behavioural and developmental interventions for autism spectrum disorder: a clinical systematic review. PLoS One, 3(11), e3755. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19015734. doi:10.1371/journal.pone.0003755
Pinggera, A., Lieb, A., Benedetti, B., Lampert, M., Monteleone, S., Liedl, K. R., . . . Striessnig, J. (2015). CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biol Psychiatry, 77(9), 816-822. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25620733. doi:10.1016/j.biopsych.2014.11.020
Rebellato, P., Kaczynska, D., Kanatani, S., Rayyes, I. A., Zhang, S., Villaescusa, C., . . . Uhlen, P. (2019). The T-type Ca(2+) Channel Cav3.2 Regulates Differentiation of Neural Progenitor Cells during Cortical Development via Caspase-3. Neuroscience, 402, 78-89. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30677486. doi:10.1016/j.neuroscience.2019.01.015
Richdale, A. L., & Schreck, K. A. (2009). Sleep problems in autism spectrum disorders: prevalence, nature, & possible biopsychosocial aetiologies. Sleep Med Rev, 13(6), 403-411. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19398354. doi:10.1016/j.smrv.2009.02.003
Rosti, R. O., Sadek, A. A., Vaux, K. K., & Gleeson, J. G. (2014). The genetic landscape of autism spectrum disorders. Dev Med Child Neurol, 56(1), 12-18. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24116704. doi:10.1111/dmcn.12278
Rudolph, U., & Knoflach, F. (2011). Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov, 10(9), 685-697. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21799515. doi:10.1038/nrd3502
Scholl, U. I., Stolting, G., Nelson-Williams, C., Vichot, A. A., Choi, M., Loring, E., . . . Lifton, R. P. (2015). Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife, 4, e06315. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25907736. doi:10.7554/eLife.06315
Seagar, M., & Takahashi, M. (1998). Interactions between presynaptic calcium channels and proteins implicated in synaptic vesicle trafficking and exocytosis. J Bioenerg Biomembr, 30(4), 347-356. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9758331.
Simms, B. A., & Zamponi, G. W. (2014). Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron, 82(1), 24-45. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24698266. doi:10.1016/j.neuron.2014.03.016
Soghomonian, J. J., & Martin, D. L. (1998). Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci, 19(12), 500-505. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9871412.
Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., . . . Keating, M. T. (2004). Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell, 119(1), 19-31. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15454078. doi:10.1016/j.cell.2004.09.011
Splawski, I., Yoo, D. S., Stotz, S. C., Cherry, A., Clapham, D. E., & Keating, M. T. (2006). CACNA1H mutations in autism spectrum disorders. J Biol Chem, 281(31), 22085-22091. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16754686. doi:10.1074/jbc.M603316200
Strom, S. P., Stone, J. L., Ten Bosch, J. R., Merriman, B., Cantor, R. M., Geschwind, D. H., & Nelson, S. F. (2010). High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol Psychiatry, 15(10), 996-1005. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19455149. doi:10.1038/mp.2009.41
Swanberg, S. E., Nagarajan, R. P., Peddada, S., Yasui, D. H., & LaSalle, J. M. (2009). Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. Hum Mol Genet, 18(3), 525-534. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19000991. doi:10.1093/hmg/ddn380
Szabo, G., Katarova, Z., Kortvely, E., Greenspan, R. J., & Urban, Z. (1996). Structure and the promoter region of the mouse gene encoding the 67-kD form of glutamic acid decarboxylase. DNA Cell Biol, 15(12), 1081-1091. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/8985122.
Talley, E. M., Cribbs, L. L., Lee, J. H., Daud, A., Perez-Reyes, E., & Bayliss, D. A. (1999). Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci, 19(6), 1895-1911. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10066243.
Uzunova, G., Pallanti, S., & Hollander, E. (2016). Excitatory/inhibitory imbalance in autism spectrum disorders: Implications for interventions and therapeutics. World J Biol Psychiatry, 17(3), 174-186. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26469219. doi:10.3109/15622975.2015.1085597
Valicenti-McDermott, M., McVicar, K., Rapin, I., Wershil, B. K., Cohen, H., & Shinnar, S. (2006). Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr, 27(2 Suppl), S128-136. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16685179.
van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., . . . Kwiatkowski, D. J. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science, 277(5327), 805-808. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9242607.
Vinkers, C. H., & Olivier, B. (2012). Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators? Adv Pharmacol Sci, 2012, 416864. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22536226. doi:10.1155/2012/416864
Vithayathil, J., Pucilowska, J., & Landreth, G. E. (2018). Chapter 3 - ERK/MAPK signaling and autism spectrum disorders. In A. Shekhar (Ed.), Progress in Brain Research (Vol. 241, pp. 63-112): Elsevier.
Vorstman, J. A., Staal, W. G., van Daalen, E., van Engeland, H., Hochstenbach, P. F., & Franke, L. (2006). Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry, 11(1), 1, 18-28. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16205736. doi:10.1038/sj.mp.4001757
Wang, H., Bedford, F. K., Brandon, N. J., Moss, S. J., & Olsen, R. W. (1999). GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton. Nature, 397(6714), 69-72. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9892355. doi:10.1038/16264
Watanabe, M., & Fukuda, A. (2015). Development and regulation of chloride homeostasis in the central nervous system. Front Cell Neurosci, 9, 371. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26441542. doi:10.3389/fncel.2015.00371
Wheeler, D. B., Randall, A., & Tsien, R. W. (1996). Changes in action potential duration alter reliance of excitatory synaptic transmission on multiple types of Ca2+ channels in rat hippocampus. J Neurosci, 16(7), 2226-2237. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/8601803.
White, S. W., Oswald, D., Ollendick, T., & Scahill, L. (2009). Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol Rev, 29(3), 216-229. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19223098. doi:10.1016/j.cpr.2009.01.003
Williams, M. E., Washburn, M. S., Hans, M., Urrutia, A., Brust, P. F., Prodanovich, P., . . . Stauderman, K. A. (1999). Structure and functional characterization of a novel human low-voltage activated calcium channel. J Neurochem, 72(2), 791-799. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9930755.
Yang, M., Abrams, D. N., Zhang, J. Y., Weber, M. D., Katz, A. M., Clarke, A. M., . . . Crawley, J. N. (2012). Low sociability in BTBR T+tf/J mice is independent of partner strain. Physiol Behav, 107(5), 649-662. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22245067. doi:10.1016/j.physbeh.2011.12.025
Yi, J. J., & Ehlers, M. D. (2007). Emerging roles for ubiquitin and protein degradation in neuronal function. Pharmacol Rev, 59(1), 14-39. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17329546. doi:10.1124/pr.59.1.4
Zhubi, A., Chen, Y., Guidotti, A., & Grayson, D. R. (2017). Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects. Int J Dev Neurosci, 62, 63-72. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28229923. doi:10.1016/j.ijdevneu.2017.02.003