Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies

Abstract

Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized ASD studies from the beginning of 1990, has been further developed by the comparative analyses of the research and clinical reports, which have grown progressively in recent years up to late 2023. The tools necessary for the identification of the ASD disease and its related clinical pathologies are genetic and epigenetic mutations affected by the specific interaction with transcription factors and chromatin remodeling processes occurring within specific complexes of brain neurons. Most often, the ensuing effects induce the inhibition/excitation of synaptic structures sustained primarily, at dendritic fibers, by alterations of flat and spine response sites. These effects are relevant because synapses, established by specific interactions of neurons with glial cells, operate as early and key targets of ASD. The pathology of children is often suspected by parents and communities and then confirmed by ensuing experiences. The final diagnoses of children and mature patients are then completed by the combination of neuropsychological (cognitive) tests and electro-/magneto-encephalography studies developed in specialized centers. ASD comorbidities, induced by processes such as anxieties, depressions, hyperactivities, and sleep defects, interact with and reinforce other brain diseases, especially schizophrenia. Advanced therapies, prescribed to children and adult patients for the control of ASD symptoms and disease, are based on the combination of well-known brain drugs with classical tools of neurologic and psychiatric practice. Overall, this review reports and discusses the advanced knowledge about the biological and medical properties of ASD.

Keywords: arborization; dendrite; dysgenesis; flat; haploinsufficiency; organoid; pre-/post-synapse; pre-school; spine; subtype.

Figure 1

Examples of two types of dendrite arborization emerging from similar neuronal cell bodies and examples of dendritic spines. In (A), all dendritic fibers appear smooth because their post-synaptic structures, largely predominant in inhibitory neurons, are flat, i.e., they do not emerge or emerge only marginally from the fiber surface. In (B), the dendritic fibers predominant in stimulatory neurons are largely covered by spines, i.e., small stemming protrusions connected to fibers by their necks. (A,B) contain modified versions of Figure 1 from our previous publication [7]. (C) shows a fraction of an original figure by Santiago Ramon y Cajal (1896) (CAT 024, book Ciencia y Arte by the Instituto Cajal, Madrid, 2004) showing the heterogeneity of the spines emerging from dendritic fibers of pyramidal cells, illustrating in particular their variability in size, shape, density and distribution.

Figure 2

ARID1B acts as a scaffolding protein that holds together the components of its complex ability to operate with specific chromatin components of reactive genes. (A,C) images illustrate two cells (orange) characterized by flat and spiny dendritic fibers, respectively. In the nucleus (violet) of these images, the ARID1B complex regulates the transcription of specific genes. The generated mRNA transcripts (small black dots) are transferred to the cytoplasm of the corresponding proteins addressed to the dendritic fibers (red arrows). In (A), the latter proteins contribute to the appropriate assembly of flat post-synaptic structures. The bottom (B) is analogous to (A) except that ARID1B has been knocked-down, the red pointed arrows do not move specific mRNAs, small white dots contain proteins different from those generated by ARID1B, the post-synapses are absent, and the pre-synapses are scattered in the space. (C) is like (A) except for one spine with black dots assembled close to two pre-synapses assembling whole synapses; (D) corresponds to (C) without ARID1B; thus, it is analogous to (B) with respect to (A). The change in (D) versus (C) is the tiny spine to which pre-synapses assemble to establish the whole synapse.