Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

Abstract

60Background: Although habituation is one of the most ancient and fundamental forms of learning, its 61 regulators and relevance for human disease are poorly understood. 62Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or 63 without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested 64 these models in light-off jump habituation. We dissected neuronal substrates underlying the 65 identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and 66 interaction networks to determine the clinical features and molecular processes that are associated 67 with habituation deficits. 68Results: We identified more than 100 genes required for habituation learning. For the vast majority 69 of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize 70 ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the 71 Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit 72 increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular 73 level, ID genes required for normal habituation are enriched in synaptic function and converge on 74Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK 75 signaling in cholinergic neurons specifically inhibit the adaptive habituation response. 76Conclusions: Our work supports the relevance of habituation learning to autism, identifies an 77 unprecedented number of novel habituation players, supports an emerging role for inhibitory 78 neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK 79 signaling. This establishes habituation as a possible, widely applicable functional readout and target 80 for pharmacologic intervention in ID/ASD. 81 82 described in a fraction of ASD individuals (9-11), but has not been connected yet to specific genetic 96 defects, with a single exception. Recently, two independent studies demonstrated habituation 97 deficits in patients with Fragile X syndrome, the most common monogenic cause of intellectual 98 disability (ID) and ASD (12, 13), confirming previously reported habituation deficits in Fmr1 KO mice 99 (14, 15). Habituation deficits have also been reported in a limited number of other ID or ASD 100 (ID/ASD) disease models (16)(17)(18)(19). 101Because assessing human gene function in habituation is challenging, we utilized a cross-102 species approach. We apply light-off jump habituation in Drosophila to increase our knowledge on 103 the genetic control of habituation and, at the same time, to address the relevance of decreased 104 habituation in ID and in comorbid ASD disorders. Since ID is present in 70% of individuals with ASD 105 (20), monogenic causes of ID provide a unique molecular windows to ASD pathology (21). Drosophila 106 is a powerful, well-established model for ID (22)(23)(24) and offers genome-wide resources to st...

Early Differences in Auditory Processing Relate to Autism Spectrum Disorder Traits in Infants with Neurofibromatosis Type 1

“…Failure to attenuate responses to repetition or to respond selectively to a change in auditory input could compromise language development Benasich & Tallal, 2002) and may also relate to broader aspects of cognitive inflexibility, which has been noted in several neurodevelopmental disorders including ASD, Prader-Willi, Rett Syndrome and Fragile X (American Psychiatric Association, 2013; Lewis & Kim, 2009;McDiarmid et al, 2019;Oakes et al, 2016). Further, failure in these basic learning mechanisms may indicate alterations in neural organisation, consistent with observations of atypical neural connectivity in developmental disorders as well as differences in the coordination of excitation and inhibition (Delbruck et al, 2019;Ethridge et al, 2016;Linke et al, 2018;Rubenstein & Merzenich, 2003).…”

Conserved regulation of neurodevelopmental processes and behavior by FoxP in Drosophila

“…These defects might contribute to symptoms associated with defective cortical filtering, such as sensory hypersensitivity and other ASD features [98, 99]. In recent years, studies in Drosophila but also in other organisms have reported habituation deficits as a widely affected mechanism in models of ID/ASD disorders [100, 101]. Whether habituation deficits contribute to cognitive and learning defects observed in FOXP patients remains to be investigated.…”

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

“…Different types of habituation have been described in Drosophila , and a variety of assays are available for their assessment (Asztalos et al, 2007; Das et al, 2011; Kuntz et al, 2012; Paranjpe et al, 2012). Recently, Drosophila knockdown models of ∼300 ID genes were investigated in the light-off jump habituation paradigm (Box 1), revealing habituation deficits in more than 100 models (Fenckova et al, 2018). Interestingly, among the habituation-defective ID models, those with comorbid ASD were particularly enriched, suggesting that habituation could be a widely applicable readout for Drosophila studies of both disorders.…”