臺灣博碩士論文加值系統

The voltage-dependent calcium channels (VDCCs) trigger many intracellular biochemical events, including muscle contraction, regulation of gene expression, and secretion of hormones and neurotransmitters. Of all the VDCCs, the T-type Ca2+ channel α1H subunit encoded by Cav3.2 (Cacna1h) gene is highly expressed in the hippocampus, which is correlated with contextual learning and spatial memory. In this thesis, I present evidences to demonstrate that Cav3.2-/- mice are impaired in social interaction, cognitive function, and novelty-induced anxiety. All these phenotypes represent the autism spectrum disorder (ASD)-like symptoms. Functional analysis of CACNA1H mutations have been reported that several mutations reduce Cav3.2 channel activity in ASD patients. However, the underlying mechanism remains unclear. Since the GABA/glutamate imbalance has been found in various models of ASD, in addition, our published microarray study shows that GABA-related genes, including Egr1 (Early growth response protein 1) and Gabarap (Gamma-aminobutyric acid receptor-associated protein), are significantly downregulated in the Cav3.2-/- mice, this research thus aims to investigate whether the ASD-like phenotypes in the Cav3.2-/- mice are regulated by GABA. I treated the Cav3.2-/- mice with low-dose clonazepam, which increase GABAergic transmission by acting as GABA-positive allosteric modulator. Results showed that behavior deficits in social novelty and contextual memory retrieval are improved by clonazepam, suggesting GABA might play a critical role in social interaction and cognitive function. Our results reveal that Cacna1h knockout mice exhibit autistic-like behaviors due to abnormal GABAergic transmission and clonazepam injection can reverse the behavioral deficits. Further electrophysiological recording and molecular/cellular experiments are necessary to confirm the findings.

Preface I
Abstract II
Index III
INTRODUCTION 1
-AUTISM SPECTRUM DISORDERS (ASDs) 1
-α1H (CaV3.2) T-TYPE CALCIUM CHANNEL 2
-ASSOCIATION BETWEEN ASDs AND VDCCs 3
-α1H (CaV3.2) T-TYPE CALCIUM CHANNEL KNOCKOUT MICE 4
-EXCITATORY/INHIBITORY IMBALANCE IN ASDs 5
-CaV3.2 CHANNEL AND GLUTAMATERGIC/GABAERGIC TRANSMISSION 6
AIM 6
MATERIALS AND METHODS 7
-ANIMALS 7
-DRUG ADMINISTRATION 7
-LOCOMOTOR ACTIVITY IN THE OPEN FIELD 7
-CENTER TIME IN OPEN FIELD TEST 8
-SELF-GROOMING BEHAVIOR 8
-ELEVATED PLUS-MAZE (EPM) 8
-MARBLE BURYING 9
-TRACE FEAR CONDITIONING 9
-CONTEXTUAL TEST 10
-THREE-CHAMBER SOCIAL INTERACTION ASSAY 10
-RNA EXTRACTION 11
-REVERSE TRANSCRIPTION (RT) 12
-QRT-PCR (QUANTITATIVE REAL-TIME PCR) 13
-WESTERN BLOT ANALYSIS 14
-STATISTICS 17
RESULTS 18
DISCUSSION 22
FIGURES AND TABLES 27
HYPOTHESIS AND FUTURE WORKS 53
REFERENCES 54

Agoston, A., Kunz, L., Krieger, A., & Mayerhofer, A. (2004). Two types of calcium channels in human ovarian endocrine cells: involvement in steroidogenesis. J Clin Endocrinol Metab, 89(9), 4503-4512. doi:10.1210/jc.2003-032219
American Psychiatric Association. (2013). Autism Spectrum Disorder Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC.
Angoa-Perez, M., Kane, M. J., Briggs, D. I., Francescutti, D. M., & Kuhn, D. M. (2013). Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp(82), 50978. doi:10.3791/50978
Bannai, H., Niwa, F., Sherwood, M. W., Shrivastava, A. N., Arizono, M., Miyamoto, A., . . . Mikoshiba, K. (2015). Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium. Cell Rep, 13(12), 2768-2780. doi:10.1016/j.celrep.2015.12.002
Baranek, G. T. (2002). Efficacy of sensory and motor interventions for children with autism. J Autism Dev Disord, 32(5), 397-422.
Barbosa, R., Scialfa, J. H., Terra, I. M., Cipolla-Neto, J., Simonneaux, V., & Afeche, S. C. (2008). Tryptophan hydroxylase is modulated by L-type calcium channels in the rat pineal gland. Life Sci, 82(9-10), 529-535. doi:10.1016/j.lfs.2007.12.011
Basu, S. N., Kollu, R., & Banerjee-Basu, S. (2009). AutDB: a gene reference resource for autism research. Nucleic Acids Res, 37(Database issue), D832-836. doi:10.1093/nar/gkn835
Bean, B. P. (1989). Classes of calcium channels in vertebrate cells. Annu Rev Physiol, 51, 367-384. doi:10.1146/annurev.ph.51.030189.002055
Beaudet, A. L. (2007). Autism: highly heritable but not inherited. Nat Med, 13(5), 534-536. doi:10.1038/nm0507-534
Bhat, S., Dao, D. T., Terrillion, C. E., Arad, M., Smith, R. J., Soldatov, N. M., & Gould, T. D. (2012). CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol, 99(1), 1-14. doi:10.1016/j.pneurobio.2012.06.001
Broekkamp, C. L., Rijk, H. W., Joly-Gelouin, D., & Lloyd, K. L. (1986). Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice. Eur J Pharmacol, 126(3), 223-229.
Buescher, A. V., Cidav, Z., Knapp, M., & Mandell, D. S. (2014). Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr, 168(8), 721-728. doi:10.1001/jamapediatrics.2014.210
Burket, J. A., Benson, A. D., Tang, A. H., & Deutsch, S. I. (2013). D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res Bull, 96, 62-70. doi:10.1016/j.brainresbull.2013.05.003
Carbone, E., & Lux, H. D. (1984). A low voltage-activated calcium conductance in embryonic chick sensory neurons. Biophys J, 46(3), 413-418. doi:10.1016/S0006-3495(84)84037-0
Catterall, W. A. (2000). Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol, 16, 521-555. doi:10.1146/annurev.cellbio.16.1.521
Catterall, W. A. (2011). Voltage-gated calcium channels. Cold Spring Harb Perspect Biol, 3(8), a003947. doi:10.1101/cshperspect.a003947
Catterall, W. A., & Few, A. P. (2008). Calcium channel regulation and presynaptic plasticity. Neuron, 59(6), 882-901. doi:10.1016/j.neuron.2008.09.005
Chandra, D., Jia, F., Liang, J., Peng, Z., Suryanarayanan, A., Werner, D. F., . . . Homanics, G. E. (2006). GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci U S A, 103(41), 15230-15235. doi:10.1073/pnas.0604304103
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. 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. doi:10.1371/journal.pone.0029384
Chen, Y., Lu, J., Pan, H., Zhang, Y., Wu, H., Xu, K., . . . Wu, X. (2003). Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol, 54(2), 239-243. doi:10.1002/ana.10607
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. doi:10.1177/0883073810393964
Christensen, D. L., Bilder, D. A., Zahorodny, W., Pettygrove, S., Durkin, M. S., Fitzgerald, R. T., . . . Yeargin-Allsopp, M. (2016). Prevalence and Characteristics of Autism Spectrum Disorder Among 4-Year-Old Children in the Autism and Developmental Disabilities Monitoring Network. J Dev Behav Pediatr, 37(1), 1-8. doi:10.1097/DBP.0000000000000235
Chung, N. C., Huang, Y. H., Chang, C. H., Liao, J. C., Yang, C. H., Chen, C. C., & Liu, I. Y. (2015). Behavior training reverses asymmetry in hippocampal transcriptome of the cav3.2 knockout mice. PLoS One, 10(3), e0118832. doi:10.1371/journal.pone.0118832
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. doi:10.1038/ejhg.2015.21
Dixon, C. I., Rosahl, T. W., & Stephens, D. N. (2008). Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates. Pharmacol Biochem Behav, 90(1), 1-8. doi:10.1016/j.pbb.2008.01.015
Dolphin, A. C. (2003). Beta subunits of voltage-gated calcium channels. J Bioenerg Biomembr, 35(6), 599-620.
Eckle, V. S., Shcheglovitov, A., Vitko, I., Dey, D., Yap, C. C., Winckler, B., & Perez-Reyes, E. (2014). Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J Physiol, 592(4), 795-809. doi:10.1113/jphysiol.2013.264176
Egashira, N., Okuno, R., Abe, M., Matsushita, M., Mishima, K., Iwasaki, K., . . . Fujiwara, M. (2008). Calcium-channel antagonists inhibit marble-burying behavior in mice. J Pharmacol Sci, 108(1), 140-143.
Fassio, A., Patry, L., Congia, S., Onofri, F., Piton, A., Gauthier, J., . . . Cossette, P. (2011). SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet, 20(12), 2297-2307. doi:10.1093/hmg/ddr122
Flavell, S. W., & Greenberg, M. E. (2008). Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci, 31, 563-590. doi:10.1146/annurev.neuro.31.060407.125631
Folstein, S. E., & Rosen-Sheidley, B. (2001). Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet, 2(12), 943-955. doi:10.1038/35103559
Francis, A., Msall, M., Obringer, E., & Kelley, K. (2013). Children with autism spectrum disorder and epilepsy. Pediatr Ann, 42(12), 255-260. doi:10.3928/00904481-20131122-10
Francois, A., Schuetter, N., Laffray, S., Sanguesa, J., Pizzoccaro, A., Dubel, S., . . . Bourinet, E. (2015). The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function. Cell Rep. doi:10.1016/j.celrep.2014.12.042
Gackiere, F., Bidaux, G., Delcourt, P., Van Coppenolle, F., Katsogiannou, M., Dewailly, E., . . . Mariot, P. (2008). CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. J Biol Chem, 283(15), 10162-10173. doi:10.1074/jbc.M707159200
Gangarossa, G., Laffray, S., Bourinet, E., & Valjent, E. (2014). T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants. Front Behav Neurosci, 8, 92. doi:10.3389/fnbeh.2014.00092
Ganz, M. L. (2007). The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med, 161(4), 343-349. doi:10.1001/archpedi.161.4.343
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.
Gatto, C. L., & Broadie, K. (2010). Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci, 2, 4. doi:10.3389/fnsyn.2010.00004
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. 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. doi:10.1038/nature11356
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. doi:10.1111/j.1442-9071.2005.00987.x
Hudmon, A., & Schulman, H. (2002). Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem J, 364(Pt 3), 593-611. doi:10.1042/BJ20020228
Iftinca, M. C., & Zamponi, G. W. (2009). Regulation of neuronal T-type calcium channels. Trends Pharmacol Sci, 30(1), 32-40. doi:10.1016/j.tips.2008.10.004
Isaacson, J. S., & Strowbridge, B. W. (1998). Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron, 20(4), 749-761.
Jacquemont, M. L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., . . . Philippe, A. (2006). Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet, 43(11), 843-849. doi:10.1136/jmg.2006.043166
Kedia, S., & Chattarji, S. (2014). Marble burying as a test of the delayed anxiogenic effects of acute immobilisation stress in mice. J Neurosci Methods, 233, 150-154. doi:10.1016/j.jneumeth.2014.06.012
Kim, Y. S., Leventhal, B. L., Koh, Y. J., Fombonne, E., Laska, E., Lim, E. C., . . . Grinker, R. R. (2011). Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry, 168(9), 904-912. doi:10.1176/appi.ajp.2011.10101532
Kocovska, E., Biskupsto, R., Carina Gillberg, I., Ellefsen, A., Kampmann, H., Stora, T., . . . Gillberg, C. (2012). The rising prevalence of autism: a prospective longitudinal study in the Faroe Islands. J Autism Dev Disord, 42(9), 1959-1966. doi:10.1007/s10803-012-1444-9
Krey, J. F., & Dolmetsch, R. E. (2007). Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol, 17(1), 112-119. doi:10.1016/j.conb.2007.01.010
Lee, E., Lee, J., & Kim, E. (2017). Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders. Biol Psychiatry, 81(10), 838-847. doi:10.1016/j.biopsych.2016.05.011
Lee, E. J., Choi, S. Y., & Kim, E. (2015). NMDA receptor dysfunction in autism spectrum disorders. Curr Opin Pharmacol, 20, 8-13. doi:10.1016/j.coph.2014.10.007
Leyfer, O. T., Folstein, S. E., Bacalman, S., Davis, N. O., Dinh, E., Morgan, J., . . . Lainhart, J. E. (2006). Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. J Autism Dev Disord, 36(7), 849-861. doi:10.1007/s10803-006-0123-0
Lu, A. T., Dai, X., Martinez-Agosto, J. A., & Cantor, R. M. (2012). Support for calcium channel gene defects in autism spectrum disorders. Mol Autism, 3(1), 18. doi:10.1186/2040-2392-3-18
Luscher, B., Fuchs, T., & Kilpatrick, C. L. (2011). GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron, 70(3), 385-409. doi:10.1016/j.neuron.2011.03.024
Ma, D. Q., Whitehead, P. L., Menold, M. M., Martin, E. R., Ashley-Koch, A. E., Mei, H., . . . Pericak-Vance, M. A. (2005). Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet, 77(3), 377-388. doi:10.1086/433195
Manning-Courtney, P., Murray, D., Currans, K., Johnson, H., Bing, N., Kroeger-Geoppinger, K., . . . Johnson, A. (2013). Autism spectrum disorders. Current problems in pediatric and adolescent health care, 43(1), 2-11.
Matson, J. L. (2016). History and Purpose of Assessment and Diagnosis of Autism Handbook of Assessment and Diagnosis of Autism Spectrum Disorder: Springer International Publishing.
Matson, J. L., & Shoemaker, M. (2009). Intellectual disability and its relationship to autism spectrum disorders. Res Dev Disabil, 30(6), 1107-1114. doi:10.1016/j.ridd.2009.06.003
McDougle, C. J., Holmes, J. P., Carlson, D. C., Pelton, G. H., Cohen, D. J., & Price, L. H. (1998). A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry, 55(7), 633-641.
McKay, B. E., McRory, J. E., Molineux, M. L., Hamid, J., Snutch, T. P., Zamponi, G. W., & Turner, R. W. (2006). Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur J Neurosci, 24(9), 2581-2594. doi:10.1111/j.1460-9568.2006.05136.x
McKernan, R. M., & Whiting, P. J. (1996). Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci, 19(4), 139-143.
Mo, J., Kim, C. H., Lee, D., Sun, W., Lee, H. W., & Kim, H. (2015). Early growth response 1 (Egr-1) directly regulates GABAA receptor alpha2, alpha4, and theta subunits in the hippocampus. J Neurochem, 133(4), 489-500. doi:10.1111/jnc.13077
Nelson, S. B., & Valakh, V. (2015). Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron, 87(4), 684-698. doi:10.1016/j.neuron.2015.07.033
Nicolson, R., Awad, G., & Sloman, L. (1998). An open trial of risperidone in young autistic children. J Am Acad Child Adolesc Psychiatry, 37(4), 372-376. doi:10.1097/00004583-199804000-00014
Njung'e, K., & Handley, S. L. (1991). Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol, 104(1), 105-112.
Nowycky, M. C., Fox, A. P., & Tsien, R. W. (1985). Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature, 316(6027), 440-443.
Oswald, D. P., & Sonenklar, N. A. (2007). Medication use among children with autism spectrum disorders. J Child Adolesc Psychopharmacol, 17(3), 348-355. doi:10.1089/cap.2006.17303
Pang, R. D., Wang, Z., Klosinski, L. P., Guo, Y., Herman, D. H., Celikel, T., . . . Holschneider, D. P. (2011). Mapping functional brain activation using [14C]-iodoantipyrine in male serotonin transporter knockout mice. PLoS One, 6(8), e23869. doi:10.1371/journal.pone.0023869
Parner, E. T., Thorsen, P., Dixon, G., de Klerk, N., Leonard, H., Nassar, N., . . . Glasson, E. J. (2011). A comparison of autism prevalence trends in Denmark and Western Australia. J Autism Dev Disord, 41(12), 1601-1608. doi:10.1007/s10803-011-1186-0
Perez-Reyes, E. (2003). Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev, 83(1), 117-161. doi:10.1152/physrev.00018.2002
Raud, S., Sutt, S., Luuk, H., Plaas, M., Innos, J., Koks, S., & Vasar, E. (2009). Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABA(A) receptors in Wfs1-deficient mice. Neurosci Lett, 460(2), 138-142. doi:10.1016/j.neulet.2009.05.054
Schoppa, N. E., Kinzie, J. M., Sahara, Y., Segerson, T. P., & Westbrook, G. L. (1998). Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J Neurosci, 18(17), 6790-6802.
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., . . . Wigler, M. (2007). Strong association of de novo copy number mutations with autism. Science, 316(5823), 445-449. doi:10.1126/science.1138659
Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., & Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry, 47(8), 921-929. doi:10.1097/CHI.0b013e318179964f
Snutch, T. P., Peloquin, J., Mathews, E., & McRory, J. E. (2005). Molecular properties of voltage-gated calcium channels Voltage-gated calcium channels (pp. 61-94): Springer.
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. 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. doi:10.1038/mp.2009.41
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.
Tamada, K., Tomonaga, S., Hatanaka, F., Nakai, N., Takao, K., Miyakawa, T., . . . Takumi, T. (2010). Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling. PLoS One, 5(12), e15126. doi:10.1371/journal.pone.0015126
Wang, G., Bochorishvili, G., Chen, Y., Salvati, K. A., Zhang, P., Dubel, S. J., . . . Zhu, J. J. (2015). CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy. Genes Dev, 29(14), 1535-1551. doi:10.1101/gad.260869.115
Williams, K., Brignell, A., Randall, M., Silove, N., & Hazell, P. (2013). Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev(8), CD004677. doi:10.1002/14651858.CD004677.pub3
Williams White, S., Keonig, K., & Scahill, L. (2007). Social skills development in children with autism spectrum disorders: a review of the intervention research. J Autism Dev Disord, 37(10), 1858-1868. doi:10.1007/s10803-006-0320-x
Wing, L., & Gould, J. (1979). Severe impairments of social interaction and associated abnormalities in children: Epidemiology and classification. Journal of Autism and Developmental Disorders, 9(1), 11-29. doi:10.1007/BF01531288
Won, H., Lee, H. R., Gee, H. Y., Mah, W., Kim, J. I., Lee, J., . . . Kim, E. (2012). Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature, 486(7402), 261-265. doi:10.1038/nature11208