Different Arrangement of Dopamine Receptors/NMDA Receptors Heterocomplexes in the Brain Regions of a Healthy Male, Female and Audiogenic Seizure-Prone Male Rats

Differences in the composition and subcellular localization of heteroreceptors in the brain can trigger central nervous system diseases, including epilepsy and autism. Protein-protein interactions between Dopamine Receptors (DRs) and GLUN2A and GLUN2B subunits are critical mechanisms that regulate dopamine and glutamate coordinated signals. These interactions may be involved in the pathophysiological predisposition of epilepsy. We hypothesized that the specificity of dopaminergic neurotransmission in audiogenic Seizure-Prone (SP) rats could be underlined by the distribution and expression of the N-Methyl-D-Aspartate Glutamate Receptor (NMDAR) and Dopamine Receptor (NMDAR/DR) heterocomplex. We determined the oligomerization of synaptic and extra-synaptic NMDAR subunits with D1 and D2 receptors in the prefrontal cortex and Nucleus Accumbens (NAc) of healthy and epileptic males rats. Considering that the comorbidity of epilepsy and autism is more prevalent in females, we also studied the pattern of interaction. in NMDAR/DR heterocomplex formation in healthy female rats. The association of Dopamine Receptor type 1 (D1R) with the GLUN2A receptor, in the extra-synaptic fraction of epilepsy-prone rats, was lower than that in healthy female and male rats. In contrast, the interaction of D1R with the GLUN2B receptor was higher in the extra-synaptic membranes of epilepsy-prone rats than that in healthy rats. Furthermore, we found that the D2R/GLUN2B ratio was higher in the synaptic NAc fraction of SP and female rats. Therefore, we suggest that the different subunit proportions of the NMDAR/DR heterocomplex in the prefrontal cortex and NAc of male, female, and SP rats can be attributed to their cognitive or emotional flexibility.