Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders

“…These outcomes may be compared between cell models derived from individuals with or without a respective genetic risk factor (iPSC-models), or—in a more standardised and less individualised fashion—specific knockouts are compared to wild-type neural cell models. Regarding animal models, besides brain morphological, gene expression, and functional outcomes over development, social communication outcomes may also be studied, such as sociability, social novelty, or ultrasonic vocalization [ 13 ]. Still, the interpretation of these results in relation to children, youth, and adults with ASD is a major challenge, which has been discussed by recent reviews taking different approaches, such as gene-based [ 14 ] or function-based [ 15 ] approaches.…”

“…For example, the role of mutations in the mTOR or RAS signalling pathways show similar neuropathological characteristics in human and rodent models [ 16 ]. Gene expression pattern, neural synaptic function, or the imbalance of inhibitory and excitatory neural functions are other well-studied aspects which can be compared between rodent and human models [ 13 , 17 , 18 ]. Additionally, the role of somatic mutations has been the focus of recent exciting developments, especially in the field of treatment-resistant epilepsy, as documented both in humans and in animal models [ 19 , 20 ].…”

“…The availability of known compounds with certain functions is crucial here. Several papers in the present Special Issue discuss these ideas, for example, through presenting possible new pharmacological options for carriers of specific genetic syndromes [ 13 , 22 ], or the authors translate neurobiological findings in relation to specific genetic syndromes into clinical care [ 23 ]. Finally, in addition to drug repurposing, gene therapies also may be developed in the future as new treatment option for ASD [ 24 ].…”

Keeping Excitation–Inhibition Ratio in Balance

“…Despite the accumulating data on factors, including genetic, immune, environmental, and associated with neurodevelopmental and psychiatric disorders, the underlying mechanisms leading to the manifestation of symptoms remain poorly understood [ 1 , 2 ]. As the anatomy of the brain seems to not be dramatically changed in the case of many brain disorders, recent data showing that some unrelated genetic mutations can result in the manifestation of quite similar phenotypes—for instance, social behavioral deficits—suggest that the main cause of symptoms is the way neurons communicate, i.e., a disturbance of neuronal network activity.…”

From Genes to Therapy in Autism Spectrum Disorder

“…The study of the behavioral phenotypes in mouse models of these genes generates relevant information that cannot be easily obtained in human carriers of these variants, feeding essential information into the efforts towards novel pharmacological interventions [ 30 ]. Illustrating this principle, their observations in Shank3 , Nrxn1 and Cntnap2 knockout mice indicate that many of the phenotypic abnormalities are detectable early in life.…”