Early Serotonergic Projections to Cajal-Retzius Cells: Relevance for Cortical Development

Abstract

Although the serotonergic system plays an important role in various neurological disorders, the role of early serotonergic projections to the developing cerebral cortex is not well understood. Because serotonergic fibers enter the marginal zone (MZ) before birth, it has been suggested that they may influence cortical development through synaptic contacts with Cajal-Retzius (CR) cells. We used immunohistochemistry combined with confocal and electron microscopy to show that the earliest serotonergic projections to the MZ form synaptic contacts with the somata and proximal dendrites of CR cells as early as embryonic day 17. To elucidate the functional significance of these early serotonergic contacts with CR cells, we perturbed their normal development by injecting pregnant mice with 5-methoxytryptamine. Lower reelin levels were detected in the brains of newborn pups from the exposed animals. Because reelin plays an important role in the cortical laminar and columnar organization during development, we killed some pups from the same litters on postnatal day 7 and analyzed their presubicular cortex. We found that the supragranular layers of the presubicular cortex (which normally display a visible columnar deployment of neurons) were altered in the treated animals. Our results suggest a mechanism of how serotonergic abnormalities during cortical development may disturb the normal cortical organization; and, therefore, may be relevant for understanding neurological disorders in which abnormalities of the serotonergic system are accompanied by cortical pathology (such as autism).

The N-terminal region of reelin regulates postnatal dendritic maturation of cortical pyramidal neurons

“…For example, the reeler mouse, an autosomal recessive mutant in which reelin is defective, displays abnormalities in presubicular columns, which led Nishikawa et al (16) to postulate that reelin may act as a stop signal for dendritic extensions of cortical neurons. In addition, Janusonis et al (17) showed that serotonergic input on Cajal-Retzius cells is important for proper corticogenesis, as disruption of the serotonergic system during embryonic development results in lower levels of whole-brain reelin and a disturbed formation of cortical columns in the presubicular cortex. However, it is not clear whether the manifestations of these postnatal abnormalities are a mere consequence of the absence of reelin during the embryonic stage, or whether a different postnatal mechanism is responsible for the changes in cortical column formation.…”

Neonatal serotonin depletion alters behavioral responses to spatial change and novelty

“…In cerebral cortical development, early manipulations of the serotonergic innervation lead to altered development and plasticity in sensory areas in a variety of species (Gu and Singer, 1995;Osterheld-Haas and Hornung, 1996;Janusonis et al, 2004). In rat, neonatal systemic depletion of the cortical serotonergic innervation delays thalamocortical patterning (Blue et al, 1991) and diminishes the size of the barrel field area during the first postnatal week (Bennett-Clarke et al, 1994).…”

Reelin glycoprotein: structure, biology and roles in health and disease

“…More interestingly, several experimental paradigms and haploinsufficiency in Reln gene in mice also cause decreases in Reelin production with resultant cortical and behavioral abnormalities. 18,[39][40][41] In the heterozygous reeler mutation, there is a 50% reduction in Reelin protein and mRNA, decrease in dendritic spine density in frontal cortex, neuropil hypoplasticity, decreased GAD67 expression and decreased GABA turnover. 42 Additionally, the heterozygous reeler mutant mice exhibit decreased prepulse inhibition, 40 a phenomenon observed in schizophrenia and autism.…”

“…45 Finally, exposure of rat pups to 5 methoxytryptamine leads to reductions in brain and blood Reelin levels, and abnormal corticogenesis. 41 Analogies between these animal models and development of schizophrenia and autism will be made and correlations will be discussed in the following passages.…”

“…However, these authors 76 felt that 'association studies of DNA variations are often ineffective in addressing functional alteration of gene products at the level of gene expression' and suggested additional biochemical studies of brain and blood products to further assess the involvement of Reln gene in autism. Despite the controversial nature of genetic association studies, Rakic and coworkers 41 have developed a potential animal model for autism which links prenatal serotonergic abnormalities to reduced brain and blood Reelin levels and abnormal brain development, indicating the relevance of biochemical/neuroanatomic studies pertaining to Reelin signaling system in autism.…”