Abstract:

Brain activity is regulated by gene expression, and altered gene expression can reflect the transformed brain state. With the development of brain imaging genomics, it is now possible to detect genomic changes associated with brain structure and function, combined with the functional magnetic resonance imaging (fMRI) and transcriptome analysis across cortical regions. At present, this research approach has been gradually applied to neuropsychiatric diseases, including autism spectrum disorders (ASD), to explore the relationship between gene expression and brain activity. The study of the mechanism of genes related to brain activity in the pathogenesis of ASD can provide physiological reference for the analysis of brain activity changes, the exploration of pathogenesis and the development of clinical treatment strategies of ASD patients. In this review, we summarized the differences in brain structure and function between ASD patients and healthy individuals, and the important genes related to these differences, including ANK2, CD38, CHD2, CHD7, CHD8, CNTNAP2, DIP2A, SHANK3, OXTR, GABRQ and SCN1B. According to their specific functions, we divide these genes into four categories: neural development, synaptic transmission, neurotransmitters and excitation-inhibition balance.

ANK2 mutations in patients with ASD can lead to social behavior disorders associated with higher executive functions, that’s because ANK2 is a regulator of early neurogenesis which regulates neural stem cell differentiation and neuronal migration, and its expression level affects the expression of other genes involved in neural development. CD38 deficiency in ASD patients can induce dysfunction of PI3K/AKT pathway, which affects normal neuronal growth and migration. CHD2, CHD7 and CHD8 are involved in the development of brain progenitors, the cortex and brain regions through different transcription factors. CNTNAP2, an ASD risk gene mainly affecting frontal lobe connectivity, functions to participate in the dendritic growth of cortical interneurons. ANK2, CD38, CHD2, CHD7, CHD8 and CNTNAP2, these genes all affect the brain structure and function of patients with ASD by participating in the process of neural development, so they are classified as neural development. DIP2A interacts with postsynaptic actin binding proteins, and its absence results in defective dendritic spine morphology, altered postsynaptic density structure, reduced number of synaptic transmission, reduced amplitude of miniature excitatory postsynaptic current and decrease of cortical acetylation, ultimately it will affect the excitability of brain activity. SHANK3 encodes multi-domain scaffold proteins in postsynaptic densification, which plays an important role in synaptic formation and dendritic spine maturation. Both DIP2A and SHANK3 act on the synaptic structure of neurons, and cause related symptoms of ASD by affecting the synaptic transmission function of neurons. The OXTR encodes the oxytocin receptor protein, which influences the binding of the neurotransmitter oxytocin, and which in turn affects brain activity in ASD patients. The down-regulation of GABRQ expression can reduce the number of GABA receptor subunits in parietal lobe, cerebellum and frontal lobe, and affect the activity of GABA-mediated neurons in the neural circuits of brain, which is the physiological basis of the excitation-inhibition imbalance of cerebral cortex in ASD patients. SCN1B of ASD patients is abnormally expressed in PV+ inhibitory interneurons, resulting in the abnormal activity of PV+ inhibitory interneurons in the cortex, which triggers a cortical excitation-inhibitory imbalance, and subsequently leads to cognitive and emotional disorders. GABRQ and SCN1B cause related symptoms in patients with ASD by affecting the excitation-inhibition balance of the cerebral cortex.

ASD is a complex multi-gene and multi-factor disease. The extensive phenotype of ASD is related to the mutation and deletion of one or a group of related genes, and is affected by environmental, social and other external factors. We classified the pathogenic mechanism of these risk genes into four different categories. Although some genes have cross-effects in different categories, it has more practical significance to take refined analysis for investigating how different genes affect brain activity and ASD pathogenesis, and also it provides potential ideas for treatment.

Key words: autism, brain imaging, brain activity, gene expression