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.
Highlights
Autism spectrum disorder (ASD) is a complex lifelong neurodevelopmental condition that is characterized by difficulties with social interaction and communication, and by repetitive, restricted, and stereotyped behaviors
Two major clusters are genes involved in gene regulation by influencing protein translation or transcription (MECP2, CHD8, PTEN, FMR1), and genes involved in synaptic function (NRXN1, NRLGN, CNTNAP2, SHANK3) [19,20]
We will describe the current findings using the examples of three established genetic mouse modes of synapse dysfunction, Nrnx1, Cntnap2, and Shank3, which are all linked to ASD [16]
Summary
Autism spectrum disorder (ASD) is a complex lifelong neurodevelopmental condition that is characterized by difficulties with social interaction and communication, and by repetitive, restricted, and stereotyped behaviors. Two major clusters are genes involved in gene regulation by influencing protein translation or transcription (MECP2, CHD8, PTEN, FMR1), and genes involved in synaptic function (NRXN1, NRLGN, CNTNAP2, SHANK3) [19,20] Such gene clusters could possibly reveal convergence in biological functions and underlying neurodevelopmental processes [19]. Of the above-mentioned clusters, the synaptic proteins are of particular interest, as they are heavily involved in shaping synaptic connections by regulating synaptic formation, function, and maintenance Establishing such neuronal connections is especially important during development when functioning brain circuits are formed. This group of synaptic proteins includes various cell adhesion molecules such as the presynaptic neurexin.
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