PSA-NCAM Colocalized with Cholecystokinin-Expressing Cells in the Hippocampus Is Involved in Mediating Antidepressant Efficacy

Abstract

The extracellular glycan polysialic acid linked to neural cell adhesion molecule (PSA-NCAM) is principally expressed in the developing brain and the adult neurogenic regions. Although colocalization of PSA-NCAM with cholecystokinin (CCK) was found in the adult brain, the role of PSA-NCAM remains unclear. In this study, we aimed to elucidate the functional significance of PSA-NCAM in the CA1 region of the male mouse hippocampus. Combined fluorescence in situ hybridization and immunohistochemistry showed that few vesicular glutamate transporter 3-negative/CCK-positive (VGluT3 -/CCK ϩ ) cells were colocalized with PSA-NCAM, but most of the VGluT3 ϩ / CCK ϩ cells were colocalized with PSA-NCAM. The somata of PSA-NCAM ϩ /CCK ϩ cells were highly innervated by serotonergic boutons than those of PSA-NCAM Ϫ /CCK ϩ cells. The expression ratios of 5-HT 3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM ϩ /CCK ϩ cells than in PSA-NCAM Ϫ /CCK ϩ cells. Pharmacological digestion of PSA-NCAM impaired the efficacy of antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor, but not the efficacy of benzodiazepine anxiolytic diazepam. A Western blot showed that restraint stress decreased the expressions of p11 and mature brain-derived neurotrophic factor (BDNF), and FLX increased them. Interestingly, the FLX-induced elevation of expression of p11, but not mature BDNF, was impaired by the digestion of PSA-NCAM. Quantitative reverse transcription-polymerase chain reaction showed that restraint stress reduced the expression of polysialyltransferase ST8Sia IV and FLX elevated it. Collectively, PSA-NCAM colocalized with VGluT3 ϩ /CCK ϩ cells in the CA1 region of the hippocampus may play a unique role in the regulation of antidepressant efficacy via the serotonergic pathway.

Transcriptional landscape of the dorsal raphe serotonin neurons rendering stress resiliency

“…Apparently contradicting our result, it has been reported that S100a10 knockout mice showed depressive-like symptoms 46 and S100a10 protein and mRNA in the cortex and hippocampus are known to increase after SSRI administration and decrease in both a mouse model of depression and depressive patients 40, [59][60][61][62] . On the other hand, S100a10 was significantly upregulated by chronic restraint stress in the lateral habenula 63 , the same as our result of DRN serotonin neurons.…”

A Preliminary Investigation on Plasma Cell Adhesion Molecules Levels by Protein Microarray Technology in Major Depressive Disorder

“…These results were validated in some clinical studies. One clinical investigation has detected increased levels of NrCAM in the cerebrospinal fluid (CSF) of patients with unipolar depressive disorder (27). However, this was not in line with the findings from Hidese et al (20), which found NCAM was down-regulated in CSF of MDD compared with heathy controls (20).…”

“…The reasons for this discrepancy could be due to sample size, disease course, use of antidepressants, and protein determination techniques. Some studies have shown that the function of NrCAM depends on its glycosylation, in particular polysalification, known as polysialic acid (PSA) ( 28 ). There is growing evidence which support the importance of polysialylated NCAM (PSA-NCAM) in MDD ( 19 ).…”