The hippocampal glycome contributes to behavioural phenotype in a novel rodent model of mood disorders

O'Connor AM, Pardo T, Birt I, Hagenauer MH, Maras PM, Prater KE, Blandino P, Hebda-Bauer EK, Watson SJ Jr, Akil H
Society for Neuroscience. 2018.


Bred High-Responder (bHR) and bred Low-Responder (bLR) rats present a novel rodent model of mood disorders. bHR animals emulate externalising mood disorders, and bLR animals emulate internalising mood disorders. bLRs have lower Fibroblast Growth Factor 2 (FGF2) expression within the hippocampus than bHRs. Early-life administration of FGF2 reverses this deficit, and also alters the bLR behavioural phenotype. Membrane-bound Heparan Sulfate Proteoglycans (HSPGs) mediate FGF2 binding with FGF Receptor-1 (FGFR1), particularly Syndecan-4 (Sdc4) and Glypican-1 (Gpc1). This study investigates the hippocampal HSPG profiles of bHR and bLR animals and the behavioural impact of altering the hippocampal glycome.

Materials and Methods: Hippocampi were collected from male animals of the bHR and bLR colonies, homogenised and processed using RNA sequencing. Whole brain tissue was collected from adult male animals, and P14 male and female animals at baseline and with vehicle/FGF2 administered on postnatal day 1. Tissue was sectioned at 10μm, and in situ hybridisation for Gpc1 and Sdc4 performed using radioisotope labelling. Immunohistochemistry was performed on perfused brain tissue against Sdc4, Gpc1, GFAP and NeuN.

Results: RNA Sequencing data revealed that Sdc4 and Gpc1 are differentially expressed within the bHR and bLR hippocampus. In situ hybridisation was used to confirm these results, revealing that bLR animals express greater levels of Gpc1 than bHR animals throughout all hippocampal regions and the basolateral amygdala at all ages assessed, and that Sdc4 was more highly expressed in juvenile bLR and adult bHR hippocampus. P1 FGF2 administration altered the expression patterns at P14 of both Gpc1 and Sdc4 in the bLR line and Sdc4 in the bHR line. Immunohistochemistry revealed that Gpc1 is expressed in neurons within the rodent hippocampus.

Discussion: bHR and bLR animals demonstrate differential HSPG profiles within the hippocampus, which are modulated by early-life FGF2 administration. These results suggest that not only do bLR animals express less FGF2 within the hippocampus than their bHR counterparts, but that the signalling activity of FGF2-FGF Receptor-1 within this brain region is potentially altered. Studies are currently underway to alter the hippocampal glycome and determine the impact on emotional behaviours of bLR and bHR animals.!/4649/presentation/34749