Abstract
BackgroundCentral nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets.ResultsOnly 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR.ConclusionA number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.
Highlights
Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure
To better understand the molecular mechanisms associated with neurodegenerative processes after injury, we first examined the survival of neurons in the ganglion cell layer (GCL) after acute axonal trauma by histological examination of the retinas over an extended 28day period, which is a well-established time line for retinal ganglion cell (RGC) death [19]
Survival of neurons and specificity of gene expression changes following optic nerve crush (ONC) There was a progressive decrease of neurons in the retinal ganglion cell layer (RGCL) following ONC as assessed by Nissl stained retinal flat mounts (Additional file 1: Figure S1A)
Summary
Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular events resulting in extensive damage to neurons [1,2,3,4,5]. Changes in gene expression in rodent ONC models have been previously studied [22,26,27,28,29,30] and include gap associated protein 43 (Gap43) [31,32,33], glial fibrillary acidic protein (Gfap) [34,35,36] and neurofilament deregulation after crush injury [37]. Multiple injury models have been utilized to assess the fate of RGCs after ocular injuries that include ischemia/reperfusion, ON irradiation, ON transections, and traumatic ON injury in rodent and primate models [22,30,46,47,48,49,50]
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