Transcription profiling of spastic glycine receptor b mutant spinal cord through a time series to study the molecular events underlying phenotypic discordance in glycine receptor defect mice.

ABSTRACT: Summary: We build a model for the molecular and cellular events underlying phenotypic discordance in glycine receptor defects (beta subunit). Some mice progress and die, while their littermates recover and get better, despite the same mutation on an inbred genetic background. We find evidence for glycine neurotransmitter toxicity and loss of glycinergic interneurons early in the disease, but some mice are able to keep things going until they can over-express homomeric alpha1 channels, whereupon they recover. In the mice progressing towards lethality, neurotransmitter toxicity too quickly extends to GABAergic interneurons and motorneurons, and they lose their window of time to upregulate the alpha1 glycine receptor, and they crash and burn. Importantly, human patients with glycine receptor defects typically show a resolution of their phenotype with age, and we propose that the same remodeling events are occuring in human patients. Hypothesis: Our data suggests that functional recovery of GlyRb mutant mice is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia (mutations of glycine receptors) show remodeling similar to that of the recovering spastic mice, as human patients also show a lessening of symptoms as a function of age. Specific Aim: Murine models for human Startle Disease show clinical variability between littermates. Here, we determined the molecular remodeling of spastic GlyRb mutant spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. At young ages, all animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the GlyRa1 subunit, and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express GlyRa1, and also showed relative loss of gephyrin. These molecular changes were associated with preferential loss of GABAergic interneurons, and extensive motorneuron loss.

ORGANISM(S): Mus musculus

DISEASE(S): mild early symptoms

SUBMITTER: Eric Hoffman 

PROVIDER: E-GEOD-1800 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress