Exploring perspectives of Dscam for cognitive deficits: a review of multifunction for regulating neural wiring in homeostasis

Abstract

Down syndrome cell adhesion molecule (Dscam) represents a group of cell surface transmembrane receptors with a conserved protein structure across species. In Drosophila, Dscam exhibits extensive isoform diversity resulting from alternative splicing, providing each cell with a unique identity. Identical isoforms expressing on the surfaces of opposing cells mediate homophilic interactions, thereby driving intracellular signaling for establishment of complex neuronal branching patterns. Mammalian Dscam lacks isoform diversity but retains the homophilic binding property. In contrast, it is capable of mediating multifaced neurological functions which are more complex than those of Drosophila Dscam. In this review, we spotlight that the homeostatic mechanisms mediated by Dscam are significant for normal cognitive function. Down syndrome (DS) and autism spectrum disorders (ASD) are two common neurodevelopmental diseases, the cognitive deficits of which are frequently correlated with aberrant DSCAM expression. Previous studies have presented some evidence that the neural homeostatic mechanisms associated with DSCAM are compromised in these two diseases. However, the insight into DSCAM-mediated homeostatic plasticity remains seriously overlooked. Furthermore, recent studies put forward that DSCAM might be one of the key molecules involved in neuronal age-related mechanisms during early stage of Alzheimer's disease (AD), a neurodegenerative disease linked to aberrant homeostatic mechanisms. In this review, we aim to provide a comprehensive understanding of Dscam-mediated crucial roles in regulating neural circuitry for homeostasis, thus elucidating how Dscam induces changes of homeostatic plasticity to affect cognitive function in either physiological or pathological conditions. We hope this review could inspire future studies to test the extent to which Dscam-mediated neural homeostatic mechanisms contribute to neurological disorders accompanied by cognitive deficits, thus facilitating research on discovering potential therapeutic avenues.

Keywords: Alzheimer’s disease; Dscam; cognitive deficits; homeostatic synaptic plasticity; learning and memory.

Figure 1

The mechanisms of Dscam for controlling synaptic plasticity. (A) Schematic diagram elucidating the local mechanism by which Dscam mediates homeostatic synaptic plasticity at presynaptic sites. At the growth cones of axons, the preponderant amount of Dscam migrates and becomes anchored to the postsynaptic elements, thereby facilitating synaptic transmission (depicted by blue arrows) (Li et al., 2009). Meanwhile, a residual small fraction of Dscam is retained locally within the presynaptic varicosities, serving to modulate the stability of these presynaptic structures (indicated by red arrows) (Li et al., 2009). Notably, both Dscam deficiency and overexpression scenarios are correlated with enlarged presynaptic terminals, albeit with differential impacts on glutamatergic transmission. In the case of Dscam deficiency, due to the compromised regulation of presynaptic varicosity stability, there is an upsurge in spontaneous glutamatergic transmission and accelerated neuronal maturation (Chen et al., 2022; Kim et al., 2013). Conversely, Dscam overexpression leads to an impairment of effective glutamatergic transmission (Liu et al., 2023). Additionally, the local translation of presynaptic Dscam constitutes an essential mechanism underpinning axon outgrowth (Montesinos, 2017). (B) Schematic diagram explicating the local mechanism through which Dscam mediates homeostatic synaptic plasticity at postsynaptic sites. Dscam is positioned on the membrane surfaces of both pre-and post-synaptic compartments. It establishes trans-synaptic connections by promoting the clustering of AMPA receptors (AMPAR) at the postsynaptic membrane (as illustrated on the left). Upon stimulation, the membrane localizations of both AMPAR and NMDA receptors (NMDAR) increase within the postsynaptic compartment, a process regulated by Dscam (depicted on the right) (Li et al., 2009). Subsequent to the trans-synaptic interaction of Dscam, its intracellular domain is cleaved and released into the cytoplasm. Subsequently, it is efficiently transported into the nucleus by specific nuclear import proteins, ultimately resulting in altered expression of synapse-related genes (represented by blue arrows) (Sachse et al., 2019). Furthermore, the alterations in postsynaptic NMDARs driven by Dscam would initiate the remodeling of presynaptic Dscam as well as the local translation of postsynaptic Dscam, thereby regulating synaptic plasticity to maintain homeostasis (indicated by red dashed arrows) (Li et al., 2009).

Figure 2

Unresolved questions between Dscam and several common neurological diseases. The human DSCAM gene is located on chromosome band 21q22.2-22.3. Studies showed that aberrant DSCAM expression may be responsible for the cognitive deficits in a subset of patients with Down syndrome (DS) and autism spectrum disorders (ASD). Generally, the expression of DSCAM is elevated in the patients of Down syndrome whereas downregulated in the patients of autism spectrum disorder. Both diseases are heterogeneous in etiology and phenotype, leading to several unresolved issues in this research area, including the pathological contributions of DSCAM? DSCAM-associated phenotypes of disease? Interactions between disease-causing gene/proteins? In addition, Dscam is also reported to be increased in the brain region of patients with Alzheimer’s disease (AD) and corresponding mouse models. Particularly, immunoreactivity for DSCAM is localized to regions associated with senile plaque formation, implicating that DSCAM may involve in the early stage of AD pathology. However, whether DSCAM mediates compensatory mechanisms during AD’s early stage or accelerates AD pathology is still unclear. We argue that a profound understanding of Dscam-mediated homeostatic plasticity can offer crucial insights into how DSCAM contributes to cognitive deficits in these diseases, thereby advancing our ability to tackle these unresolved questions.