Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

Xinkun Wang,Xiaodong Bao,Abdulbaki Agbas,Elias K Michaelis,Ranu Pal

doi:10.1186/1471-2164-11-360

Abstract

BackgroundIncreases during aging in extracellular levels of glutamate (Glu), the major excitatory neurotransmitter in the brain, may be linked to chronic neurodegenerative diseases. Little is known about the molecular responses of neurons to chronic, moderate increases in Glu levels. Genome-wide gene expression in brain hippocampus was examined in a unique transgenic (Tg) mouse model that exhibits moderate Glu hyperactivity throughout the lifespan, the neuronal Glutamate dehydrogenase (Glud1) mouse, and littermate 9 month-old wild type mice.ResultsIntegrated bioinformatic analyses on transcriptomic data were used to identify bio-functions, pathways and gene networks underlying neuronal responses to increased Glu synaptic release. Bio-functions and pathways up-regulated in Tg mice were those associated with oxidative stress, cell injury, inflammation, nervous system development, neuronal growth, and synaptic transmission. Increased gene expression in these functions and pathways indicated apparent compensatory responses offering protection against stress, promoting growth of neuronal processes (neurites) and re-establishment of synapses. The transcription of a key gene in the neurite growth network, the kinase Ptk2b, was significantly up-regulated in Tg mice as was the activated (phosphorylated) form of the protein. In addition to genes related to neurite growth and synaptic development, those associated with neuronal vesicle trafficking in the Huntington's disease signalling pathway, were also up-regulated.ConclusionsThis is the first study attempting to define neuronal gene expression patterns in response to chronic, endogenous Glu hyperactivity at brain synapses. The patterns observed were characterized by a combination of responses to stress and stimulation of nerve growth, intracellular transport and recovery.

Highlights

Increases during aging in extracellular levels of glutamate (Glu), the major excitatory neurotransmitter in the brain, may be linked to chronic neurodegenerative diseases
Despite the multiple beneficial actions of Glu in the central nervous system (CNS) of mammals, it is true that excessive excitation of neurons by Glu can lead to nerve cell damage and neurological dysfunction [7]
At the age of nine months it would be possible to probe for changes in gene expression that may represent adaptive, compensatory or corrective responses of hippocampus cells to chronic Glu hyperactivity, while at the same time minimizing the impact of neuronal death on the results of gene array analyses

Summary

Introduction

Increases during aging in extracellular levels of glutamate (Glu), the major excitatory neurotransmitter in the brain, may be linked to chronic neurodegenerative diseases. Glu is released from nerve cell processes following electrical excitation, interacts with surface receptors in the synaptic region of another nerve cell, and initiates the influx of sodium and calcium ions across the membrane of the post-synaptic neuron. It was proposed that pathological states in the CNS may result from either acute or chronic excessive release of Glu and over-activation of its post-synaptic receptors [9,10,11,12,13]. This suggestion is based, primarily, on the toxicity that follows acute exposure of nerve cells to excessive excitation by Glu. But, as we pointed out previously [14], acute treatments with Glu may not fully replicate the effects of chronic, localized, moderate excess release of Glu at synapses occurring throughout the lifespan of an organism

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Results

Conclusion