Coiled-coil and C2 domain containing 1A (CC2D1A)是一個在各物種間結構高度保全的蛋白質，此蛋白最初在一個大型人類基因掃描找尋nuclear factor-B的調控子時被發現可作為其活化子。CC2D1A蛋白突變被發現會造成自閉症侯群以及智能不全，但是CC2D1A蛋白突變是如何造成大腦功能改變仍是未知的。在此我們將利用兩個不同的基因系統去研究CC2D1A在不同的發育時期所扮演的角色。首先，我們使用Cre重組酶切除loxP序列的方式在小鼠出生後的大腦興奮性神經元裡剔除CC2D1A的基因去研究CC2D1A在海馬迴的神經突觸可塑性以及認知記憶學習能力中所扮演的角色。我們發現當缺少CC2D1A時，在海馬迴CA1區域會造成神經突觸長期增益現象的維持產生毀損，並且也能發現神經型態的簡化以及記憶學習能力的異常。接著我們更發現了CC2D1A的一個新角色，CC2D1A會調控SENP1以及SENP3的表現量，並藉由影響deSUMOylation的過程去造成Rac1的高度活化。給予Rac1抑制劑(NSC23766)能夠有效的改善長期增益現象的表現以及認知學習能力。因此推知Rac1高度活化與神經突觸可塑性以及認知功能異常有高度相關。接著我們利用一個在早期胚胎時期剃除CC2D1A更模擬真實自閉症病患的方式去研究CC2D1A的角色，與出生後剔除CC2D1A的動物相比，在胚胎時期剔除CC2D1A會造成更顯著的自閉症狀譬如社交能力不全以及反覆行為。除此之外，在前額葉皮質第五層的錐狀神經細胞會觀測到興奮性與抑制性的比例上的改變、神經型態簡化以及變少的抑制性訊號傳遞。給予Minocycline治療後，能夠有效的改善自閉症狀以及神經型態與抑制性訊號傳遞的異常。這些結果指出當CC2D1A的缺少所造成的神經傳遞以及形態上的異常與自閉症侯群的症狀有高度相關。整體而言，我們發現了CC2D1A的新角色，CC2D1A會經由影響Rac1的活性去影響神經突觸可塑性以及認知功能。在早期發育時期，CC2D1A會影響神經發育以及神經訊息傳遞，當突變時將造成神經發育疾病。

Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein. In a large-scale screening of human genes, it was first identified as a nuclear factor-B activator. CC2D1A mutations results in autism spectrum disorder and autosomal recessive nonsyndromic intellectual disability. However, how CC2D1A mutations leads to alteration in brain function remains elusive. To answer this question, we took advantage of two different model to identify the role of CC2D1A in different stages. First, we used Cre/loxP recombinase-based strategy to specific delete Cc2d1a gene in excitatory neuron postnatally to examine its role in hippocampal synaptic plasticity and learning memory function. We found that Cc2d1a deletion led to impaired LTP maintenance, decreased dendritic complexity and abnormal memory performance. We further identified a novel role of CC2D1A in regulating SENP1 and SENP3 expression, which further causing Rac1 hyperactivity due to its impaired de-SUMOylation process. Bilateral microinfusion of Rac1 inhibitor (NSC23766) successfully rescued the LTP maintenance and learning memory performance, which suggesting the correlation of Rac1 hyperactivity with impaired synaptic plasticity and abnormal cognitive function. To mimic more specifically to the realistic pathological condition of autism spectrum disorder, we then generate a novel ASD model that Cc2d1a deleted at early embryonic stage. We have found a significant difference compared to postnatal cKO model, a more apparent autistic-like features including social impairment and repetitive behaviors were observable. Also, we have found a significant elevated E/I ratio, reduced GABAergic transmission and decreased dendritic complexity in mPFC layer V pyramidal neurons. Minocycline treatment successfully restored the synaptic function and structural changes and finally rescued the sociability and repetitive behavior. These results suggest a strong correlation of Cc2d1a-deficeincy-induced impaired synaptic function and neural structure in mPFC layer V pyramidal neurons to ASD features. Overall, we have revealed a novel role of CC2D1A in mediating cognitive function and synaptic plasticity through regulating Rac1 activity, and confirmed the critical role of CC2D1A in embryonic neurodevelopmental in mediating the synaptic transmission and neural morphology.

Abraham J, Fox PD, Condello C, Bartolini A, Koh S. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis. 2012;46:425-430.
Al-Tawashi A, Jung SY, Liu D, Su B, Qin J. Protein implicated in nonsyndromic mental retardation regulates protein kinase A activity. J Biol Chem. 2012;287:14644-14658.
Al-Tawashi A, Gehring C. Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. Cell Commun Signal. 2013;11:47.
Anderson SR, Romanczyk RG. Early intervention for young children with Autism: continuum-based behavioral models. J Assoc Pers Sev Handicaps. 1999;24:162-173.
Antoine MW, Langberg T, Schnepel P, Feldman DE. Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four Autism mouse models. Neuron. 2019;101:648-661.
Basel-Vanagaite L, Alkelai A, Straussberg R, Magel N, Inbar D, Mahajna M, et al. Mapping of a new locus for autosomal recessive non-syndromic mental retardation in the chromosomal region 19p13.12-p13.2: further genetic heterogeneity. J Med Genet. 2003;40:729-732.
Basel-Vanagaite L, Attia R, Yahav M, Ferland RJ, Anteki L, Walsh CA, et al. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet. 2006;43:203-210.
Bernards A, Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell. Biol. 2004;14:377-385.
Bourin M, Hascoёt M. The mouse light/dark box test. Eur J Pharmacol. 2003;463:55-65.
Castillo-Lluva S, Tatham MH, Jones RC, Jaffray EG, Edmondson RD, Hay RT, et al. SUMOylation of the GTPase Rac1 is required for optimal cell migration. Nat Cell Biol. 2010;12:1078-1085.
Chang CH, Lai LC, Cheng HC, Chen KR, Syue YZ, Lu HC, et al. TBK1-associated protein in endolysosomes (TAPE) is an innate immune regulator modulating the TLR3 and TLR4 signaling pathways. J Biol Chem. 2011;286:7043-7051.
Chen KR, Chang CH, Huang CY, Lin CY, Lin WY, Lo YC, et al. TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity. J Biol Chem. 2012;287:32216-32221.
Chini M, Pöpplau JA, Lindemann C, Carol-Perdiguer L, Hnida M, Oberländer V, et al. Resolving and rescuing developmental miswiring in a mouse model of cognitive impairment. Neuron. 2020;105:60-74.
Chou D, Huang CC, Hsu KS. Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning. Exp Neurol. 2014;255:19-29.
Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, et al. Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. Neuroscience. 2013;246:186-198.
Deacon RM. Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc. 2006;1:122-124.
Deacon RM. Assessing nest building in mice. Nat Protoc. 2006;1:1117-1119.
Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400-1413.
Emadi-Kouchak H, Mohammadinejad P, Asadollahi-Amin A, Rasoulinejad M, Zeinoddini A, Yalda A, et al. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: a double-blind, placebo-controlled, randomized trial. Int Clin Psychopharmacol. 2016;31:20-26.
Gao X, Zheng R, Ma X, Gong Z, Xia D, Zhou Q. Elevated level of PKMζ underlies the excessive anxiety in an Autism model. Front Mol Neurosci. 2019;12:291.
Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front Psychiatry. 2010;1:136.
Ghaleiha A, Alikhani R, Kazemi MR, Mohammadi MR, Mohammadinejad P, Zeinoddini A, et al. Minocycline as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind placebo-controlled trial. J Child Adolesc Psychopharmacol. 2016;26:784-791.
Gillberg C, Billstedt E. Autism and Asperger syndrome:coexistence with other clinical disorders. Acta Psychiatr Scand. 2000;102:321-330.
Gualdoni S, Albertinazzi C, Corbetta S, Valtorta F, de Curtis I.Normal levels of Rac1 are important for dendritic but not axonal development in hippocampal neurons. Biol Cell. 2007;99:455-464.
Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509-514.
Haditsch U, Leone DP, Farinelli M, Chrostek-Grashoff A, Brakebusch C, Mansuy IM, et al. A central role for the small GTPase Rac1 in hippocampal plasticity and spatial learning and memory. Mol Cell Neurosci. 2009;41:409-419.
Haditsch U, Anderson MP, Freewoman J, Cord B, Babu H, Brakebusch C, et al. Neuronal Rac1 is required for learning-evoked neurogenesis. J Neurosci. 2013;33:12229-12241.
Haettig J, Stefanko DP, Multani ML, Figueroa DX, McQuown SC, Wood MA. HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner. Learn Mem. 2011;18:71-79.
Haettig J, Sun Y, Wood MA, Xu X. Cell-type specific inactivation of hippocampal CA1 disrupts location-dependent object recognition in the mouse. Learn Mem. 2013;20:139-146.
Henley JM, Seager R, Nakamura Y, Talandyte K, Nair J, Wilkinson KA. SUMOylation of synaptic and synapse-associated proteins: An update. J Neurochem. 2021;156:145-161.
Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF. Local GABA circuit control of experiencedependent plasticity in developing visual cortex. Science. 1998;282:1504–1508.
Hill E, Berthoz S, Frith U. Brief report: cognitive processing of own emotions in individuals with Autistic spectrum disorder and in their relatives. J Autism Dev Disord. 2004;34:229-235.
Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR. Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex. 2013;23:1784-1797.
Huang CC, Hsu KS. Sustained activation of metabotropic glutamate receptor 5 and protein tyrosine phosphatases mediate the expression of (S)-3,5-dihydroxyphenylglycine-induced long-term depression in the hippocampal CA1 region. J Neurochem 2006;96:179-194.
Huang CC, Lin HJ, Hsu KS. Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex. Cereb Cortex. 2007;17:1877-1888.
Huang CC, Lin YS, Lee CC, Hsu KS. Cell type-specific expression of Eps8 in the mouse hippocampus. BMC Neurosci. 2014;15:26.
Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:83-94.
Huttner WB, Schiebler W, Greengard P, De Camilli P. Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation. J Cell Biol. 1983;96:1374-1388.
Kaufmann WE, Moser HW. Dendritc Anomalies in Disorder Associated with Mental Retardation. Cereb Cortex. 2000;10:981-991.
Kerns CM, Newschaffer CJ, Berkowitz SJ. Traumatic childhood events and Autism spectrum disorder. J Autism Dev Disord. 2015;35:3475-3486.
Kern JK, Geier DA, Sykes LK, Geier MR. Relevance of neuroinflammation and encephalitis in Autism. Front Cell Neurosci. 2015;9:519.
Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006;50:377-388.
Lee CC, Huang CC, Hsu KS. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 2011;61:867-879.
Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, et al. Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease. Sci Rep. 2014;4:7190.
Lee CC, Huang CC, Hsu KS. The phospholipid-binding protein SESTD1 negatively regulates dendritic spine density by interfering with Rac1-Trio8 signaling pathway. Sci Rep. 2015;5:13250.
Lee CZ, Yao JS, Huang Y, Zhai W, Liu W, Guglielmo BJ, et al. Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation. J Cereb Blood Flow Metab. 2006;26:1157-1164.
Lin S, Wei X, Bales KR, Paul ABC, Ma Z, Yan G, et al. Minocycline blocks bilirubin neurotoxicity and prevents hyperbilirubinemia‐induced cerebellar hypoplasia in the Gunn rat. Eur J Neurosci. 2005;22:21-27.
Lin YT, Chen CC, Huang CC, Nishimori K, Hsu KS. Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. 2017;Nat Commun 8:537.
Lin YT, Hsieh TY, Tsai TC, Chen CC, Huang CC, Hsu KS. Conditional deletion of hippocampal CA2/CA3a oxytocin receptors impairs the persistence of long-term social recognition memory in mice. J Neurosci. 2018;38:1218-1231.
Liu Y, Du S, Lv L, Lei B, Shi W, Tang Y, et al. Hippocampal activation of Rac1 regulates the forgetting of object recognition memory. Curr Biol. 2016;26:2351-2357.
Luo L, Hensch TK, Ackerman L, Barbel S, Jan LY, Jan YN. Differential effects of the Rac GTPase on Purkinje cell. Nature. 1996;379:847-840.
Manns JR, Eichenbaum H. A cognitive map for object memory in the hippocampus. Learn Mem. 2009;16:616-624.
Manzini MC, Xiong L, Shaheen R, Tambunan DE, Di Costanzo S, Mitisalis V, et al. CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis. Cell Rep. 2014;8:647-655.
Martinez LA, Tejada-Simon MV. Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus. Neuropharmacology. 2011;61:305-312.
Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, et al. Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene. 2003;22:3307-3318.
Mayford M, Siegelbaum SA, Kandel ER. Synapses and memory storage. Cold Spring Harb Perspect Biol. 2012;4:a005751.
Millar AM, Souslova T, Albert PR. The Freud-1/CC2D1A Family: Multifunctional Regulators Implicated in Mental Retardation. J Neurosci Res. 2007;85:2833-2832.
Mineur YS, Huynh LX, Crusio WE. Social behavior deficits in the Fmr1 mutant mouse. Behav Brain Res. 2006;168:172-175.
Miyazaki S, Hiraoka Y, Hidema S, Nishimori K. Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice. Biochem Biophys Res Commun. 2016;472:319-323.
Mukaetova-Ladinska EB, Arnold H, Jaros E, Perry R, Perry E. Depletion of MAP2 expression and laminar cytoarchitectonic changes in dorsolateral prefrontal cortex in adult autistic individuals. Neuropathol Appl Neurobiol. 2004;30:615-623.
Mumby DG, Glenn MJ, Nesbitt C, Kyriazis DA. Dissociation in retrograde memory for object discriminations and object recognition in rats with perirhinal cortex damage. Behav Brain Res. 2002;132:215-226.
Nakamura A, Arai H, Fujita N. Centrosomal Aki1 and cohesin function in separase-regulated centriole disengagement. J Cell Biol. 2009;187:607-614.
Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, et al. Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One. 2012;7: e42504.
Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in Autism spectrum disorders. Neuron. 2015;87:684-698.
Oaks AW, Zamarbide M, Tambunan DE, Santini E, Di Costanzo S, Pond HL, et al. Cc2d1a loss of function disrupts functional and morphological development in forebrain neurons leading to cognitive and social deficits. Cereb Cortex. 2017;27:1670-1685.
Oh D, Han S, Seo J, Lee JR, Choi J, Groffen J, et al. Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. J Neurosci. 2010;30:14134-14144.
Ou XM, Lemonde S, Jafar-Nejad H, Bown CD, Goto A, Rogaeva A, et al. Freud-1: a neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J Neurosci. 2003;23:7415-7425.
Pardo CA, Buckley A, Thurm A, Lee LC, Azhagiri A, Neville DM, et al. A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodev Disord. 2013;5:9.
Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;14:149-167.
Peng HZ, Ma LX, Lv MH, Hu T, Liu T. Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn. Neuroscience. 2016;319:183-193.
Pietropaolo S, Guilleminot A, Martin B, D'Amato FR, Crusio WE. Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice. PLoS One. 2011;6:e17073.
Powell EM, Cambell DB, Stanwood GD, Davis C, Noebels JL, Levitt P. Genetic disruption of cortical interneuron development causes region and GABA cell typespecficdeficits, epilepsy, and behavioral disfunctin. J Neurosci. 2003;2, 622–631.
Purpura DP. Dendritic spine dysgenesis and mental retardation. Science. 1971;186: 1126-1128.
Rogaeva A, Ou XM, Jafar-Nejad H, Lemonde S, Albert PR. Differential repression by freud-1/CC2D1A at a polymorphic site in the dopamine-D2 receptor gene. J Biol Chem. 2007;282:20897-20905.
Rothwell PE, Fuccillo MV, Maxeiner S, Hayton SJ, Gokce O, Lim BK, et al. Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors. Cell. 2014;158:198-212.
Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255-267.
Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH. A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 2007;10:1012-1019.
Sarge KD, Park-Sarge OK. Sumoylation and human disease pathogenesis. Trends Biochem Sci. 2009;34:200-205.
Savitz JB, Teague TK, Misaki M, Macaluso M, Wurfel BE, Meyer M, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8:27.
Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature. 2012;486:256-260.
Schmidt A, Alan H. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 2002;16:1587-1609.
Schulz J, Franke K, Frick M, Schumacher S. Different roles of the small GTPases Rac1, Cdc42, and RhoG in CALEB/NGC-induced dendritic tree complexity. J Neurochem. 2016;139:26-39.
Selimbeyoglu A, Kim CK, Inoue M, Lee SY, Hong ASO, Kauvar I, et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci Transl Med. 2017;9:eaah6733.
Seoh ML, Ng CH, Yong J, Lim L, Leung T. ArhGAP15, a novel human RacGAP protein with GTPase binding property. FEBS Lett. 2003;539:131-137.
Shi ZY, Li YJ, Zhang KJ, Gao XC, Zheng ZJ, Han N, et al. Positive association of CC2D1A and CC2D2A gene haplotypes with mental retardation in a Han Chinese population. DNA Cell Biol. 2012;31:80-87.
Sohal VS, Rubenstein JLR. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019;24:1248-1257.
Stackman RW Jr, Cohen SJ, Lora JC, Rios LM. Temporary inactivation reveals that the CA1 region of the mouse dorsal hippocampus plays an equivalent role in the retrieval of long-term object memory and spatial memory. Neurobiol Learn Mem. 2016;133:118-128.
Takeuchi T, Duszkiewicz AJ, Morris RG. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2013;369:20130288.
Tang S, Terzic B, Wang IJ, Sarmiento N, Sizov K, Cui Y, et al. Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder. Nat Commun. 2019;10:2655.
Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ, et al. Microglia in the cerebral cortex in autism. J Autism Dev Disord. 2014;42:2569-2584.
Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S, Weinberg RJ, Greenberg ME. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron. 2005;45:525-538.
Torre-ubieta LDA, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med. 2016;22:345-361.
Tyler WJ, Pozzo-Miller L. Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones. J Physiol 2003;553:497-509.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81.
Varghese M, Keshav N , Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, et al. Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol. 2017;134:537-566.
Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011;20:3093-3108.
Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature. 2012;486:261-265.
Xiao L, Hu C, Yang W, Guo D, Li C, Shen W, et al. NMDA receptor couples Rac1-GEF Tiam1 to direct oligodendrocyte precursor cell migration. Glia. 2013;61:2078-2099.
Yang M, Bozdagi O, Scattoni ML, Wöhr M, Roullet FI, Katz AM, et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci. 2012;32:6525-6541.
Yang CH, Huang CC, Hsu KS. A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes. J Neurosci. 2012;32:7550-7762.
Yang CY, Yu TH, Wen WL, Ling P, Hsu KS. Conditional deletion of CC2D1A reduces hippocampal synaptic plasticity impairs cognitive function through Rac1 hyperactivation. J Neurosci. 2019;39:4959-4975.
Yeh CM, Huang CC, Hsu KS. Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF. J Physiol 2012;590:991-1010.
Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ, et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature. 2011;477:171-178.
Yue X, Zhang C, Zhao Y, Liu J, Lin AW, Tan VM, Drake JM, Liu L, Boateng MN, Li J, Feng Z, Hu W. Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression. Genes Dev. 2017;31:1641-1654.
Zamarbide M, Oaks AW, Pond HL, Adelman JS, Manzini MC. Loss of the intellectual disability and Autism gene Cc2d1a and its homolog Cc2d1b differentially affect spatial memory, anxiety, and hyperactivity. Front Genet. 2018;9:65.
Zamarbide M, Mossa A, Munõz-Llancao P, Wilkinson MK, Pond HL, Oaks AW, et al. Male-specific cAMP signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability. Biol Psychiatry. 2019;85:760-768.
Zhang L, Zheng H, Wu R, Zhu F, Kosten TR, Zhang XY, et al. Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: Association with pro-inflammatory cytokine levels. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:69-76.
Zhao M, Li XD, Chen Z. CC2D1A, a DM14 and C2 domain protein, activates NF-B through the canonical pathway. J Biol Chem. 2010;285:24372-24380.
Zhao M, Raingo J, Chen ZJ, Kavalali ET. Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of central synapses. J Neurophysiol. 2011;105:1506-1515.