Reviewing vascular influences on neuronal migration, cortical development, and neurodevelopmental disorders: focus on autism, ADHD and schizophrenia

Abstract

During cortical development, newly born neurons migrate radially or tangentially from their origin to expand the cortex. Simultaneously, neuron-derived factors support angiogenesis, and an elaborate network of blood cerebral vessels develops in the cortex. Traditionally, blood cerebral vessels were considered to support the growing cortex or migrating neurons by providing nutrients and oxygen. However, recent studies have shed light on Endothelial cells' influence on cortical development; they guide neuronal migration by providing molecular cues and structural support. Here, we review the current understanding of how CNS cerebral vessels support neurogenesis, neuronal migration, and the formation of the six-layer cortical structure during development. Additionally, we explore current knowledge regarding the vascular role in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia.

Fig. 1. Parallel development of blood cerebral cerebral vessels and neurons in the cortex during embryonic stages.

A Pial cerebral cerebral vessels or perineural vascular plexus (PNVP) formation begins at embryonic day (E)10.5, followed by its sprouting in the developing cortex by E12.5. Moreover, by this time, a periventricular vascular plexus originates in the ventral telencephalon. At E15.5, the angiogenic sprouting completes and spreads throughout the CNS; at 17.5, these angiogenic cerebral cerebral vessels elongate and stabilize. B Simultaneously, by E10.5, the radial glial cells (neural stem cells raised from the neuroepithelial cells) divide symmetrically to increase the pool of these radial glial cells in the avascular, hypoxic zone. Later, these radial glial cells divide asymmetrically to form 1 basal progenitor and 1 neuron or 1 intermediate progenitor (E12.5). Gradually, radial cells form layers of neurons by E15.5. By E17.5, the remaining layers of neurons are formed and possess astrocytes in the developing cortex. The Cajal-al-Retzius cells could be seen at the early embryonic stage (E10.5) and gradually expand over the later developmental stages. These cells support the radial glial structure and assist neuronal migration during cortical development. Interneurons migrate along two tangential routes, located in the marginal zone (MZ) and above the subventricular zone (SVZ). As development progresses, interneurons undergo a transition to a radial-oriented migration pattern to reach their final laminar positions and integrate into neuronal circuits alongside excitatory neurons.

Fig. 2. Vascular Alterations Associated with Neurodevelopmental Disorders: Autism and Attention Deficit/Hyperactivity Disorder (ADHD).

An aberrant angiogenesis pattern is observed in ASD. Abnormal CBF is reported in both ASD and ADHD. BBB is reported to be compromised in both conditions, as identified by the lower expression of Claudin-3, -5, and -12 in ASD. In contrast, ADHD demonstrates changes with Claudin-5, occludin, ZO1, and tricellulin. Elevated levels of the inflammatory marker MMP9 are involved in both ASD and ADHD, while MMP2 is unique to ADHD. Additionally, genetic changes in 16p11.2 and SLC7A5 contribute to vascular pathology in ASD.