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Accumulation of PSA-NCAM marks nascent neurodegeneration in the dorsal hippocampus after neonatal hypoxic-ischemic brain injury in mice.

ABSTRACT: Neonatal hypoxia-ischemia (nHI) disrupts hippocampal GABAergic development leading to memory deficits in mice. Polysialic-acid neural-cell adhesion molecule (PSA-NCAM) developmentally declines to trigger GABAergic maturation. We hypothesized that nHI changes PSA-NCAM abundance and cellular distribution, impairing GABAergic development, and marking nascent neurodegeneration. Cell degeneration, atrophy, and PSA-NCAM immunoreactivity (IR) were measured in CA1 of nHI-injured C57BL6 mice related to: (i) cellular subtype markers; (ii) GAD65/67 and synatophysin (SYP), pre-synaptic markers; (iii) phospho-Ser³⁹⁶Tau, cytoskeletal marker; and (iv) GAP43, axonalregeneration marker. PSA-NCAM IR was minimal in CA1 of shams at P11. After nHI, PSA-NCAM IR was increased in injured pyramidal cells (PCs), minimal in parvalbumin (PV)⁺INs, and absent in glia. PSA-NCAM IR correlated with injury severity and became prominent in perikaryal cytoplasm at P18. GAD65/67 and SYP IRs only weakly related to PSA-NCAM after nHI. Injured phospho-Ser³⁹⁶Tau⁺ PCs and PV⁺INs variably co-expressed PSA-NCAM at P40. While PCs with cytoplasmic marginalized PSA-NCAM had increased perisomatic GAP43, those with perikaryal cytoplasmic PSA-NCAM had minimal GAP43. PSA-NCAM increased in serum of nHI-injured mice. Increased PSA-NCAM is likely a generic acute response to nHI brain injury. PSA-NCAM aberrant cellular localization may aggravate neuronal degeneration. The significance of PSA-NCAM as a biomarker of recovery from nHI and nascent neurodegeneration needs further study.

SUBMITTER: Chavez-Valdez R

PROVIDER: S-EPMC8054724 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The somata of PSA-NCAM+/CCK+ cells were highly innervated by serotonergic boutons than those of PSA-NCAM-/CCK+ cells. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ 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+/CCK+ cells in the CA1 region of the hippocampus may play a unique role in the regulation of antidepressant efficacy via the serotonergic pathway.SIGNIFICANCE STATEMENT Polysialic acid (PSA) is composed of eight or more ?2,8-linked sialic acids. Here, we examined the functional significance of polysialic acid linked to the neural cell adhesion molecule (PSA-NCAM) in the adult mouse hippocampus. Few vesicular glutamate transporter 3-negative/cholecystokinin-positive (VGluT3-/CCK+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ cells. The efficacy of antidepressants, but not anxiolytics, was impaired by the digestion of PSA-NCAM. The antidepressant-induced increase in p11 expression was inhibited following PSA-NCAM digestion. We hence hypothesize that PSA-NCAM colocalized with VGluT3+/CCK+ cells may play a unique role in regulating antidepressant efficacy.

Project description:BackgroundHypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies.MethodsIn order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90?min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24?h and 72?h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array.ResultsWe found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-? in CSF showed an upregulation at 24?h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72?h in CSF. At 24?h post-injury, we observed an increase of Edn1, Hif1-?, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72?h post-injury.ConclusionsOur work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.

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Accumulation of PSA-NCAM marks nascent neurodegeneration in the dorsal hippocampus after neonatal hypoxic-ischemic brain injury in mice.

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