Dataset Information

ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.

ABSTRACT: ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Their phenotype clearly indicates that proNGF can be a driver of neurodegeneration, including severe learning and memory behavioral deficits, cholinergic deficits, and diffuse immunoreactivity for A-beta and A-beta-oligomers. In aged TgproNGF#3 mice spontaneous epileptic-like events are detected in entorhinal cortex-hippocampal slices, suggesting occurrence of excitatory/inhibitory (E/I) imbalance. In this paper, we investigate the molecular events linking increased proNGF levels to the epileptiform activity detected in hippocampal slices. The occurrence of spontaneous epileptiform discharges in the hippocampal network in TgproNGF#3 mice suggests an impaired inhibitory interneuron homeostasis. In the present study, we detect the onset of hippocampal epileptiform events at 1-month of age. Later, we observe a regional- and cellular-selective Parvalbumin interneuron and perineuronal net (PNN) depletion in the dentate gyrus (DG), but not in other hippocampal regions of TgproNGF#3 mice. These results demonstrate that, in the hippocampus, the DG is selectively vulnerable to altered proNGF/NGF signaling. Parvalbumin interneuron depletion is also observed in the amygdala, a region strongly connected to the hippocampus and likewise receiving cholinergic afferences. Transcriptome analysis of TgproNGF#3 hippocampus reveals a proNGF signature with broad down-regulation of transcription. The most affected mRNAs modulated at early times belong to synaptic transmission and plasticity and extracellular matrix (ECM) gene families. Moreover, alterations in the expression of selected BDNF splice variants were observed. Our results provide further mechanistic insights into the vicious negative cycle linking proNGF and neurodegeneration, confirming the regulation of E/I homeostasis as a crucial mediating mechanism.

SUBMITTER: Fasulo L

PROVIDER: S-EPMC5299926 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.

Fasulo Luisa L Brandi Rossella R Arisi Ivan I La Regina Federico F Berretta Nicola N Capsoni Simona S D'Onofrio Mara M Cattaneo Antonino A

Frontiers in molecular neuroscience 20170209

ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Thei ...[more]

PMID: 28232789

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Project description: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.

Dataset Information

ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.

Publications

ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.

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