Polysialic acid is required for dopamine D2 receptor-mediated plasticity involving inhibitory circuits of the rat medial prefrontal cortex.
Decreased expression of dopamine D2 receptors (D2R), dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT) after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN) neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA-NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R influences structural plasticity of mPFC interneurons and point to PSA-NCAM as a key player in this remodeling.
Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Burjassot, Valencia, Spain.
Esther
E
Castillo-Gómez
Emilio
E
Varea
José Miguel
JM
Blasco-Ibáñez
Carlos
C
Crespo
Juan
J
Nacher
D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D039842:Neural Cell Adhesion Molecule L1 / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D012794:Sialic Acids / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism
D018491:Dopamine Agonists; D039842:Neural Cell Adhesion Molecule L1; D017448:Receptors, Dopamine D2; D012794:Sialic Acids; D016708:Synaptophysin; C021319:polysialic acid; C103469:polysialyl neural cell adhesion molecule; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1