ADHD is a common chronic neurodevelopmental disorder and is characterized by persistent inattention, hyperactivity, impulsivity and are often accompanied by learning and memory impairment. Great evidence has shown that learning and memory impairment of ADHD plays an important role in its executive function deficits, which seriously affects the development of academic, cognitive and daily social skills and will cause a serious burden on families and society. With the increasing attention paid to learning and memory impairment in ADHD, relevant research is gradually increasing. In this article, we will present the current research results of learning and memory impairment in ADHD from the following aspects. Firstly, the animal models of ADHD, which display the core symptoms of ADHD as well as with learning and memory impairment. Secondly, the molecular mechanism of has explored, including some neurotransmitters, receptors, RNAs, etc. Thirdly, the susceptibility gene of ADHD related to the learning and impairment in order to have a more comprehensive understanding of the pathogenesis. Key words: Learning and memory, ADHD, Review.

Department of Children's Health Care The 1st Affiliated Hospital of Nanjing Medical University Jiangsu Maternal and Child Health Care Hospital Nanjing Jiangsu China

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Andersen PN, Egeland J, Øie M. Learning and memory impairments in children and adolescents with attention-deficit/hyperactivity disorder. J Learn Disabil. 2013;46:453–460. doi: 10.1177/0022219412437040. PubMed DOI

Austerman J. ADHD and behavioral disorders: Assessment, management, and an update from DSM-5. Cleve Clin J Med. 2015;82:S2–7. doi: 10.3949/ccjm.82.s1.01. PubMed DOI

D’esposito M, Detre JA, Alsop DC, Shin RK, Atlas S, Grossman M. The neural basis of the central executive system of working memory. Nature. 1995;378:279–281. doi: 10.1038/378279a0. PubMed DOI

Baddeley A. Working memory and language: an overview. J Commun Disord. 2003;36:189–208. doi: 10.1016/S0021-9924(03)00019-4. PubMed DOI

Cohen R, Cohen-Kroitoru B, Halevy A, Aharoni S, Aizenberg I, Shuper A. Handwriting in children with Attention Deficient Hyperactive Disorder: role of graphology. BMC Pediatr. 2019;19:484. doi: 10.1186/s12887-019-1854-3. PubMed DOI PMC

Tibu F, Sheridan MA, Mclaughlin KA, Nelson CA, Fox NA, Zeanah CH. Disruptions of working memory and inhibition mediate the association between exposure to institutionalization and symptoms of attention deficit hyperactivity disorder. Psychol Med. 2016;46:529–541. doi: 10.1017/S0033291715002020. PubMed DOI PMC

Tibu F, Sheridan MA, Mclaughlin KA, Nelson CA, Fox NA, Zeanah CH. Reduced working memory mediates the link between early institutional rearing and symptoms of ADHD at 12 Years. Front Psychol. 2016;7:1850. doi: 10.3389/fpsyg.2016.01850. PubMed DOI PMC

Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry. 2005;57:1336–1346. doi: 10.1016/j.biopsych.2005.02.006. PubMed DOI

Phillips MS, Bing-Canar H, Shields AN, Cerny B, Chang F, Wisinger AM, Leib SI, et al. Assessment of learning and memory impairments in adults with predominately inattentive versus combined presentation attention-deficit/hyperactivity disorder. Appl Neuropsychol Adult. 2023:1–10. doi: 10.1080/23279095.2023.2169887. PubMed DOI

Peterson K, Mcdonagh MS, Fu R. Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacology (Berl) 2008;197:1–11. doi: 10.1007/s00213-007-0996-4. PubMed DOI

Quinn D. Does chirality matter? pharmacodynamics of enantiomers of methylphenidate in patients with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008;28:S62–S66. doi: 10.1097/JCP.0b013e3181744aa6. PubMed DOI

Li J, Wang Y, Zhou R, Zhang H, Yang L, Wang B, Khan S, et al. Serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet. 2005;132b:59–63. doi: 10.1002/ajmg.b.30075. PubMed DOI

Jensen V, Rinholm JE, Johansen TJ, Medin T, Storm-Mathisen J, Sagvolden T, Hvalby O, et al. N-methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience. 2009;158:353–364. doi: 10.1016/j.neuroscience.2008.05.016. PubMed DOI

Corominas-Roso M, Ramos-Quiroga JA, Ribases M, Sanchez-Mora C, Palomar G, Valero S, Bosch R, et al. Decreased serum levels of brain-derived neurotrophic factor in adults with attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol. 2013;16:1267–1275. doi: 10.1017/S1461145712001629. PubMed DOI

Eilertsen EM, Gjerde LC, Kendler KS, Røysamb E, Aggen SH, Gustavson K, Reichborn-Kjennerud T, et al. Development of ADHD symptoms in preschool children: Genetic and environmental contributions. Dev Psychopathol. 2019;31:1299–1305. doi: 10.1017/S0954579418000731. PubMed DOI

Kian N, Samieefar N, Rezaei N. Prenatal risk factors and genetic causes of ADHD in children. World J Pediatr. 2022;18:308–319. doi: 10.1007/s12519-022-00524-6. PubMed DOI

Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24:562–575. doi: 10.1038/s41380-018-0070-0. PubMed DOI PMC

Ochozková A, Mihalčíková L, Yamamotová A, Šlamberová R. Can prenatal methamphetamine exposure be considered a good animal model for ADHD? Physiol Res. 2021;70:S431–s440. doi: 10.33549/physiolres.934815. PubMed DOI PMC

Regan SL, Williams MT, Vorhees CV. Review of rodent models of attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2022;132:621–637. doi: 10.1016/j.neubiorev.2021.11.041. PubMed DOI PMC

Meneses A, Perez-Garcia G, Ponce-Lopez T, Tellez R, Gallegos-Cari A, Castillo C. Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview. Rev Neurosci. 2011;22:365–371. doi: 10.1515/rns.2011.024. PubMed DOI

Kishikawa Y, Kawahara Y, Yamada M, Kaneko F, Kawahara H, Nishi A. The spontaneously hypertensive rat/Izm (SHR/Izm) shows attention deficit/hyperactivity disorder-like behaviors but without impulsive behavior: therapeutic implications of low-dose methylphenidate. Behav Brain Res. 2014;274:235–242. doi: 10.1016/j.bbr.2014.08.026. PubMed DOI

Oades RD, Sadile AG, Sagvolden T, Viggiano D, Zuddas A, Devoto P, Aase H, et al. The control of responsiveness in ADHD by catecholamines: evidence for dopaminergic, noradrenergic and interactive roles. Dev Sci. 2005;8:122–31. doi: 10.1111/j.1467-7687.2005.00399.x. PubMed DOI

Miller EM, Pomerleau F, Huettl P, Gerhardt GA, Glaser PE. Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 2014;231:3019–29. doi: 10.1007/s00213-014-3479-4. PubMed DOI

Sterley TL, Howells FM, Russell VA. Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model. Brain Res. 2016;1641:291–305. doi: 10.1016/j.brainres.2015.11.019. PubMed DOI

Fasmer OB, Johansen EB. Patterns of motor activity in spontaneously hypertensive rats compared to Wistar Kyoto rats. Behav Brain Funct. 2016;12:32. doi: 10.1186/s12993-016-0117-9. PubMed DOI PMC

Nakamura-Palacios EM, Caldas CK, Fiorini A, Chagas KD, Chagas KN, Vasquez EC. Deficits of spatial learning and working memory in spontaneously hypertensive rats. Behav Brain Res. 1996;74:217–227. doi: 10.1016/0166-4328(95)00165-4. PubMed DOI

Yuan H, Ni X, Zheng M, Han X, Song Y, Yu M. Effect of catalpol on behavior and neurodevelopment in an ADHD rat model. Biomed Pharmacother. 2019;118:109033. doi: 10.1016/j.biopha.2019.109033. PubMed DOI

Mereu M, Contarini G, Buonaguro EF, Latte G, Managò F, Iasevoli F, De Bartolomeis A, et al. Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder. Neuropharmacology. 2017;121:179–194. doi: 10.1016/j.neuropharm.2017.04.037. PubMed DOI

Takamatsu Y, Hagino Y, Sato A, Takahashi T, Nagasawa SY, Kubo Y, Mizuguchi M, et al. Improvement of learning and increase in dopamine level in the frontal cortex by methylphenidate in mice lacking dopamine transporter. Curr Mol Med. 2015;15:245–52. doi: 10.2174/1566524015666150330144018. PubMed DOI PMC

Zhu X, Li T, Peng S, Ma X, Chen X, Zhang X. Maternal deprivation-caused behavioral abnormalities in adult rats relate to a non-methylation-regulated D2 receptor levels in the nucleus accumbens. Behav Brain Res. 2010;209:281–288. doi: 10.1016/j.bbr.2010.02.005. PubMed DOI

Morice E, Denis C, Giros B, Nosten-Bertrand M. Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background. Eur J Neurosci. 2004;20:120–126. doi: 10.1111/j.1460-9568.2004.03465.x. PubMed DOI

Meza-Aguilar DG, Boucard AA. Latrophilins updated. Biomol Concepts. 2014;5:457–478. doi: 10.1515/bmc-2014-0032. PubMed DOI

Özaslan A, Güney E, Ergün MA, Okur İ, Yapar D. CDH13 and LPHN3 gene polymorphisms in attention-deficit/hyperactivity disorder: their relation to clinical characteristics. J Mol Neurosci. 2021;71:394–408. doi: 10.1007/s12031-020-01662-0. PubMed DOI

Regan SL, Pitzer EM, Hufgard JR, Sugimoto C, Williams MT, Vorhees CV. A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats. Neurobiol Dis. 2021;158:105456. doi: 10.1016/j.nbd.2021.105456. PubMed DOI PMC

Regan SL, Hufgard JR, Pitzer EM, Sugimoto C, Hu YC, Williams MT, Vorhees CV. Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers. Neurobiol Dis. 2019;130:104494. doi: 10.1016/j.nbd.2019.104494. PubMed DOI PMC

Fallgatter AJ, Ehlis AC, Dresler T, Reif A, Jacob CP, Arcos-Burgos M, Muenke M, et al. Influence of a latrophilin 3 (LPHN3) risk haplotype on event-related potential measures of cognitive response control in attention-deficit hyperactivity disorder (ADHD) Eur Neuropsychopharmacol. 2013;23:458–468. doi: 10.1016/j.euroneuro.2012.11.001. PubMed DOI PMC

Li X, Wu X, Luo P, Xiong L. Astrocyte-specific NDRG2 gene: functions in the brain and neurological diseases. Cell Mol Life Sci. 2020;77:2461–2472. doi: 10.1007/s00018-019-03406-9. PubMed DOI PMC

Li Y, Yin A, Sun X, Zhang M, Zhang J, Wang P, Xie R, et al. Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior. J Clin Invest. 2017;127:4270–4284. doi: 10.1172/JCI94455. PubMed DOI PMC

Rhodes SM, Coghill DR, Matthews K. Methylphenidate restores visual memory, but not working memory function in attention deficit-hyperkinetic disorder. Psychopharmacology (Berl) 2004;175:319–330. doi: 10.1007/s00213-004-1833-7. PubMed DOI

Kang AM, Palmatier MA, Kidd KK. Global variation of a 40-bp VNTR in the 3′-untranslated region of the dopamine transporter gene (SLC6A3) Biol Psychiatry. 1999;46:151–160. doi: 10.1016/S0006-3223(99)00101-8. PubMed DOI

Zuschlag ZD, Compean E, Nietert P, Lauzon S, Hamner M, Wang Z. Dopamine transporter (DAT1) gene in combat veterans with PTSD: A case-control study. Psychiatry Res. 2021;298:113801. doi: 10.1016/j.psychres.2021.113801. PubMed DOI PMC

Bacanlı A, Unsel-Bolat G, Suren S, Yazıcı KU, Callı C, Aygunes Jafari D, Kosova B, et al. Effects of the dopamine transporter gene on neuroimaging findings in different attention deficit hyperactivity disorder presentations. Brain Imaging Behav. 2021;15:1103–1114. doi: 10.1007/s11682-020-00437-w. PubMed DOI

Brown AB, Biederman J, Valera E, Makris N, Doyle A, Whitfield-Gabrieli S, Mick E, et al. Relationship of DAT1 and adult ADHD to task-positive and task-negative working memory networks. Psychiatry Res. 2011;193:7–16. doi: 10.1016/j.pscychresns.2011.01.006. PubMed DOI PMC

Li Q, Lu G, Antonio GE, Mak YT, Rudd JA, Fan M, Yew DT. The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain. Neurochem Int. 2007;50:848–857. doi: 10.1016/j.neuint.2007.02.005. PubMed DOI

Yin P, Cao AH, Yu L, Guo LJ, Sun RP, Lei GF. ABT-724 alleviated hyperactivity and spatial learning impairment in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Neurosci Lett. 2014;580:142–146. doi: 10.1016/j.neulet.2014.08.008. PubMed DOI

Loo SK, Rich EC, Ishii J, Mcgough J, Mccracken J, Nelson S, Smalley SL. Cognitive functioning in affected sibling pairs with ADHD: familial clustering and dopamine genes. J Child Psychol Psychiatry. 2008;49:950–957. doi: 10.1111/j.1469-7610.2008.01928.x. PubMed DOI

Brookes KJ, Xu X, Chen CK, Huang YS, Wu YY, Asherson P. No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study. BMC Med Genet. 2005;6:31. doi: 10.1186/1471-2350-6-31. PubMed DOI PMC

Schaefer TL, Vorhees CV, Williams MT. Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness. Neuroscience. 2009;164:1431–1443. doi: 10.1016/j.neuroscience.2009.09.059. PubMed DOI PMC

González-Burgos I, Feria-Velasco A. Serotonin/dopamine interaction in memory formation. Prog Brain Res. 2008;172:603–623. doi: 10.1016/S0079-6123(08)00928-X. PubMed DOI

Salman T, Nawaz S, Waraich RS, Haleem DJ. Repeated administration of methylphenidate produces reinforcement and downregulates 5-HT-1A receptor expression in the nucleus accumbens. Life Sci. 2019;218:139–146. doi: 10.1016/j.lfs.2018.12.046. PubMed DOI

Salman T, Afroz R, Nawaz S, Mahmood K, Haleem DJ, Zarina S. Differential effects of memory enhancing and impairing doses of methylphenidate on serotonin metabolism and 5-HT1A, GABA, glutamate receptor expression in the rat prefrontal cortex. Biochimie. 2021;191:51–61. doi: 10.1016/j.biochi.2021.08.009. PubMed DOI

Zepf FD, Landgraf M, Biskup CS, Dahmen B, Poustka F, Wöckel L, Stadler C. No effect of acute tryptophan depletion on verbal declarative memory in young persons with ADHD. Acta Psychiatr Scand. 2013;128:133–141. doi: 10.1111/acps.12089. PubMed DOI

Huang X, Wang M, Zhang Q, Chen X, Wu J. The role of glutamate receptors in attention-deficit/hyperactivity disorder: From physiology to disease. Am J Med Genet B Neuropsychiatr Genet. 2019;180:272–286. doi: 10.1002/ajmg.b.32726. PubMed DOI

Maltezos S, Horder J, Coghlan S, Skirrow C, O’gorman R, Lavender TJ, Mendez MA, et al. Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Transl Psychiatry. 2014;4:e373. doi: 10.1038/tp.2014.11. PubMed DOI PMC

Bauer J, Werner A, Kohl W, Kugel H, Shushakova A, Pedersen A, Ohrmann P. Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex. World J Biol Psychiatry. 2018;19:538–546. doi: 10.1080/15622975.2016.1262060. PubMed DOI

Hiraoka Y, Sugiyama K, Nagaoka D, Tsutsui-Kimura I, Tanaka KF, Tanaka K. Mice with reduced glutamate transporter GLT1 expression exhibit behaviors related to attention-deficit/hyperactivity disorder. Biochem Biophys Res Commun. 2021;567:161–165. doi: 10.1016/j.bbrc.2021.06.057. PubMed DOI

Shikanai H, Oshima N, Kawashima H, Kimura SI, Hiraide S, Togashi H, Iizuka K, et al. N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder. Neuropsychopharmacol Rep. 2018;38:61–66. doi: 10.1002/npr2.12007. PubMed DOI PMC

Cheng J, Xiong Z, Duffney LJ, Wei J, Liu A, Liu S, Chen GJ, et al. Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors. Biol Psychiatry. 2014;76:953–962. doi: 10.1016/j.biopsych.2014.04.003. PubMed DOI PMC

Kawade HM, Borkar CD, Shambharkar AS, Singh O, Singru PS, Subhedar NK, Kokare DM. Intracellular mechanisms and behavioral changes in mouse model of attention deficit hyperactivity disorder: Importance of age-specific NMDA receptor blockade. Pharmacol Biochem Behav. 2020;188:172830. doi: 10.1016/j.pbb.2019.172830. PubMed DOI

Wilens TE, Decker MW. Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition. Biochem Pharmacol. 2007;74:1212–1223. doi: 10.1016/j.bcp.2007.07.002. PubMed DOI PMC

Guo T, Yang C, Guo L, Liu K. A comparative study of the effects of ABT-418 and methylphenidate on spatial memory in an animal model of ADHD. Neurosci Lett. 2012;528:11–15. doi: 10.1016/j.neulet.2012.08.068. PubMed DOI

Jeong HI, Ji ES, Kim SH, Kim TW, Baek SB, Choi SW. Treadmill exercise improves spatial learning ability by enhancing brain-derived neurotrophic factor expression in the attention-deficit/hyperactivity disorder rats. J Exerc Rehabil. 2014;10:162–167. doi: 10.12965/jer.140111. PubMed DOI PMC

Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol Psychiatry. 2006;59:1065–1070. doi: 10.1016/j.biopsych.2005.10.029. PubMed DOI

Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–250. doi: 10.1007/978-3-642-45106-5_9. PubMed DOI

Wang LJ, Wu CC, Lee MJ, Chou MC, Lee SY, Chou WJ. Peripheral brain-derived neurotrophic factor and contactin-1 levels in patients with attention-deficit/hyperactivity disorder. J Clin Med. 2019:8. doi: 10.3390/jcm8091366. PubMed DOI PMC

Kasem E, Kurihara T, Tabuchi K. Neurexins and neuropsychiatric disorders. Neurosci Res. 2018;127:53–60. doi: 10.1016/j.neures.2017.10.012. PubMed DOI

Zhang S, Wu D, Xu Q, You L, Zhu J, Wang J, Liu Z, et al. The protective effect and potential mechanism of NRXN1 on learning and memory in ADHD rat models. Exp Neurol. 2021;344:113806. doi: 10.1016/j.expneurol.2021.113806. PubMed DOI

Luo P, Li X, Fei Z, Poon W. Scaffold protein Homer 1: implications for neurological diseases. Neurochem Int. 2012;61:731–738. doi: 10.1016/j.neuint.2012.06.014. PubMed DOI

Hong Q, Wang YP, Zhang M, Pan XQ, Guo M, Li F, Tong ML, et al. Homer expression in the hippocampus of an animal model of attention-deficit/hyperactivity disorder. Mol Med Rep. 2011;4:705–712. PubMed

Salatino-Oliveira A, Genro JP, Polanczyk G, Zeni C, Schmitz M, Kieling C, Anselmi L, et al. Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2015;168b:162–169. doi: 10.1002/ajmg.b.32293. PubMed DOI

Ziegler GC, Ehlis AC, Weber H, Vitale MR, Zöller JEM, Ku HP, Schiele MA, et al. A common CDH13 variant is associated with low agreeableness and neural responses to working memory tasks in ADHD. Genes (Basel) 2021:12. doi: 10.3390/genes12091356. PubMed DOI PMC

Rivero O, Selten MM, Sich S, Popp S, Bacmeister L, Amendola E, Negwer M, et al. Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition. Transl Psychiatry. 2015;5:e655. doi: 10.1038/tp.2015.152. PubMed DOI PMC

Forero A, Rivero O, Wäldchen S, Ku HP, Kiser DP, Gärtner Y, Pennington LS, et al. Cadherin-13 deficiency increases dorsal raphe 5-ht neuron density and prefrontal cortex innervation in the mouse brain. Front Cell Neurosci. 2017;11:307. doi: 10.3389/fncel.2017.00307. PubMed DOI PMC

Shin EY, Lee CS, Cho TG, Kim YG, Song S, Juhnn YS, Park SC, et al. betaPak-interacting exchange factor-mediated Rac1 activation requires smgGDS guanine nucleotide exchange factor in basic fibroblast growth factor-induced neurite outgrowth. J Biol Chem. 2006;281:35954–64. doi: 10.1074/jbc.M602399200. PubMed DOI

Mccaffrey TA, St Laurent G, 3rd, Shtokalo D, Antonets D, Vyatkin Y, Jones D, Battison E, et al. Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts. BMC Med Genomics. 2020;13:160. doi: 10.1186/s12920-020-00808-8. PubMed DOI PMC

Martyn AC, Toth K, Schmalzigaug R, Hedrick NG, Rodriguiz RM, Yasuda R, Wetsel WC, et al. GIT1 regulates synaptic structural plasticity underlying learning. PLoS One. 2018;13:e0194350. doi: 10.1371/journal.pone.0194350. PubMed DOI PMC

Won H, Mah W, Kim E, Kim JW, Hahm EK, Kim MH, Cho S, et al. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat Med. 2011;17:566–572. doi: 10.1038/nm.2330. PubMed DOI

Couto JM, Gomez L, Wigg K, Ickowicz A, Pathare T, Malone M, Kennedy JL, et al. Association of attention-deficit/hyperactivity disorder with a candidate region for reading disabilities on chromosome 6p. Biol Psychiatry. 2009;66:368–75. doi: 10.1016/j.biopsych.2009.02.016. PubMed DOI PMC

Willcutt EG, Pennington BF, Smith SD, Cardon LR, Gayán J, Knopik VS, Olson RK, et al. Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder. Am J Med Genet. 2002;114:260–268. doi: 10.1002/ajmg.10205. PubMed DOI

Gabel LA, Marin I, Loturco JJ, Che A, Murphy C, Manglani M, Kass S. Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice. Genes Brain Behav. 2011;10:868–875. doi: 10.1111/j.1601-183X.2011.00727.x. PubMed DOI PMC

Matilla A, Roberson ED, Banfi S, Morales J, Armstrong DL, Burright EN, Orr HT, et al. Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. J Neurosci. 1998;18:5508–5516. doi: 10.1523/JNEUROSCI.18-14-05508.1998. PubMed DOI PMC

Rizzi TS, Arias-Vasquez A, Rommelse N, Kuntsi J, Anney R, Asherson P, Buitelaar J, et al. The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: evidence from a large collaborative study totaling 4,963 subjects. Am J Med Genet B Neuropsychiatr Genet. 2011;156:145–157. doi: 10.1002/ajmg.b.31149. PubMed DOI PMC

Lu HC, Tan Q, Rousseaux MW, Wang W, Kim JY, Richman R, Wan YW, et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017;49:527–536. doi: 10.1038/ng.3808. PubMed DOI PMC

Celestino-Soper PB, Skinner C, Schroer R, Eng P, Shenai J, Nowaczyk MM, Terespolsky D, et al. Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders. Mol Cytogenet. 2012;5:17. doi: 10.1186/1755-8166-5-17. PubMed DOI PMC

Laatikainen LM, Sharp T, Harrison PJ, Tunbridge EM. Sexually dimorphic effects of catechol-O-methyltransferase (COMT) inhibition on dopamine metabolism in multiple brain regions. PLoS One. 2013;8:e61839. doi: 10.1371/journal.pone.0061839. PubMed DOI PMC

Gothelf D, Michaelovsky E, Frisch A, Zohar AH, Presburger G, Burg M, Aviram-Goldring A, et al. Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome. Int J Neuropsychopharmacol. 2007;10:301–308. doi: 10.1017/S1461145706006699. PubMed DOI

Eisenberg J, Mei-Tal G, Steinberg A, Tartakovsky E, Zohar A, Gritsenko I, Nemanov L, et al. Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. Am J Med Genet. 1999;88:497–502. doi: 10.1002/(SICI)1096-8628(19991015)88:5<497::AID-AJMG12>3.0.CO;2-F. PubMed DOI

Jung M, Mizuno Y, Fujisawa TX, Takiguchi S, Kong J, Kosaka H, Tomoda A. The effects of COMT polymorphism on cortical thickness and surface area abnormalities in children with ADHD. Cereb Cortex. 2019;29:3902–3911. doi: 10.1093/cercor/bhy269. PubMed DOI

Jin J, Liu L, Gao Q, Chan RC, Li H, Chen Y, Wang Y, et al. The divergent impact of COMT Val158Met on executive function in children with and without attention-deficit/hyperactivity disorder. Genes Brain Behav. 2016;15:271–279. doi: 10.1111/gbb.12270. PubMed DOI

Kang P, Luo L, Peng X, Wang Y. Association of Val158Met polymorphism in COMT gene with attention-deficit hyperactive disorder: An updated meta-analysis. Medicine (Baltimore) 2020;99:e23400. doi: 10.1097/MD.0000000000023400. PubMed DOI PMC