Polysialic acid is required for dopamine D2 receptor-mediated plasticity involving inhibitory circuits of the rat medial prefrontal cortex.

Esther Castillo-Gómez,Juan Nacher,Emilio Varea,José Miguel Blasco-Ibáñez,Carlos Crespo,Kenji Hashimoto

doi:10.1371/journal.pone.0029516

Esther Castillo-Gómez, Juan Nacher + Show 4 more

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https://doi.org/10.1371/journal.pone.0029516

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Abstract

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.

Highlights

During recent years, several evidences indicate that, in addition to neurochemical alterations, changes in the structure and connectivity of neurons in the medial prefrontal cortex may underlie the pathogenesis of different psychiatric disorders, including schizophrenia and major depression [1,2]
In order to study whether PPHT treatment-induced differences on the neurochemical phenotype of polysialic acid (PSA)-NCAM expressing interneurons, the percentages of co-localization of PSA-NCAM with CB, CR or PV were determined for each animal from Control/Control and Control/PPHT group
To analyze the differences on perisomatic innervation of medial prefrontal cortex (mPFC) pyramidal neurons after treatment, values of puncta density for PSA-NCAM, GAD65/67, PV and SYN and the percentages of PV puncta co-expressing SYN were obtained from each neuron (6 neurons from each of the 6 animals of the 4 experimental groups) and analyzed by unpaired Student’s t-test or by one-way ANOVA, with the number of neurons as the ‘‘n’’

Summary

Introduction

Several evidences indicate that, in addition to neurochemical alterations, changes in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) may underlie the pathogenesis of different psychiatric disorders, including schizophrenia and major depression [1,2]. Expression of this molecule can be still observed in the adult mPFC and persists stable until old age [9,10] In this cortical region, PSANCAM is exclusively expressed by a subset of interneurons and it is found in their somata and in inhibitory elements in the neuropil [9]. Dopamine-induced changes may probably take place through the action of D2 receptors (D2R), which are expressed in PSA-NCAM expressing interneurons of the mPFC, since D2R agonists, such as 2-(N-Phenethyl-N-propyl) amino-5hydroxytetralin hydrochloride (PPHT), increased PSA-NCAM expression and D2R antagonists (haloperidol) decreased it This modulation of PSA-NCAM expression occurs in parallel to changes in the expression of synaptic proteins and molecules related to inhibitory neurotransmission, which strongly suggests the involvement of PSA-NCAM in the plasticity of prefrontocortical inhibitory circuits [12]

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