Aberrant Dopamine Receptor Signaling Plays Critical Role in the Impairment of Striatal Neurons in Experimental Cerebral Malaria

One-fourth survivors of cerebral malaria (CM) retain long-term cognitive and behavioral deficits. Structural abnormalities in striatum are reported in 80% of children with CM. Dopamine receptors (D1 and D2) are widely expressed in striatal medium spiny neurons (MSNs) that regulate critical physiological functions related to behavior and cognition. Dysregulation of dopamine receptors alters the expression of downstream proteins such as dopamine- and cAMP-regulated phosphoprotein (DARPP), Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα), and p25/cyclin-dependent kinase 5 (cdk5). However, the role of dopamine receptor signaling dysfunction on the outcome of striatal neuron degeneration is unknown underlying the pathophysiology of CM. Using experimental CM (ECM), the present study attempted to understand the role of aberrant dopamine receptor signaling and its possible relation in causing MSNs morphological impairment. The effect of antimalarial drug artemether (ARM) rescue therapy was also assessed after ECM on the outcome of dopamine receptors downstream signaling. ECM was induced in C57BL/6 mice (male and female) infecting with Plasmodium berghei ANKA (PbA) parasite that reiterates the clinical setting of CM. We demonstrated that ECM caused a significant increase in the expression of D1, D2 receptors, phosphorylated DARPP, p25, cdk5, CaMKIIα, and D1-D2 heteromers. A substantial increase in neuronal damage observed in the dorsolateral striatum region of ECM brains (particularly in MSNs) as revealed by increased Fluoro-Jade C staining, reduced dendritic spine density, and impaired dendritic arborization with varicosities. While the ARM rescue therapy significantly altered the effects of ECM induced dopamine receptor signaling dysfunction and neurodegeneration. Overall, our data suggest that dysregulation of dopamine receptor signaling plays an important role in the degeneration of MSNs, and the ARM rescue therapy might provide better insights to develop effective therapeutic strategies for CM.