ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice: a microarray study in proNGF-overexpressing transgenic mouse. Mus musculus

The NGF precursor proNGF has conflicting effects compared to NGF, depending also on the panel of receptors expressed by target cells; although in physiological conditions proNGF is the most abundant form in the brain, it is known to increase further in Alzheimer’s Disease (AD) cortex, relative to mature NGF. The correct balance between the levels and signaling of mature NGF and its precursor proNGF, are therefore critical factors in maintaining brain homeostasis. In a previous study, we demonstrated that proNGF\NGF imbalance determines Abeta peptide processing, neurodegeneration and learning and memory deficit in lines of transgenic mice (TgproNGF#3 and TgproNGF#72) expressing postnatally furin-resistant proNGF in the neuronal compartment. In this work, we analyzed the hippocampal transcriptional profile of TgproNGF#3 mice before and in early and late phases of neurodegeneration, demonstrating that proNGF imbalance induces a broad down-regulation of transcripts, including mRNAs relevant for synaptic transmission and extracellular matrix (ECM) components, essential in shaping plasticity. Consistently, the aberrantly down-regulated transcription profile underlies a functional deficit in long-term potentiation (LTP) in the dentate gyrus (DG) and an alteration of the excitatory/inhibitory (E\I) balance, as revealed by spontaneous epileptiform events detected by multi-electrode arrays (MEA) in the entorhinal cortex-hippocampal (EC-HP) network. A greatly reduced number of parvalbuminergic interneurons was observed in the DG, accompanied by alterations in the expression of selected BDNF splice variants. Selective and region-specific progressive alterations of the interneuron\perineuronal net (PNN) system are detected in the DG accompanied, in aged mice, by depletion of calbindin in granule cells. Since the onset of spontaneous discharges in the EC-HP network precedes the transcript profile changes and the plasticity deficit, we conclude that changes in E\I homeostasis are a primary consequenceof unbalanced proNGF\NGF signaling. Overall design: Transcriptional profile (mRNAs) was measured in the brain hippocampus of TgproNGF#3 mice, a model of proNGF over-expression, at 1, 3 and 12 months of age. In each time point 4 TgproNGF#3 samples were compared to 4 corresponding Wild Type (strain C57Bl/6xDBA/2) except the 12m timepoint which has 3 replicates.