Gene Expression Profiling in Perilesional and Contralateral Areas after Ischemia in Rat Brain

Structural and functional reorganization in the vicinity of damaged neocortex and other connected brain areas seems to be responsible for postlesional functional recovery. To better understand the molecular mechanisms underlying this type of plasticity, gene expression patterns were analyzed by using DNA macroarrays comprising 1176 genes. Circumscribed unilateral infarcts consistently affecting the forelimb area of the motor cortex were induced photochemically in adult rats. Ten days after lesioning, cortical gene expression fingerprints were evaluated from an area adjacent to the lesion as well as two contralateral areas of motor and somatosensory cortex. Discrete regions showed distinct expression patterns. Upregulation was observed of different members of transcription factors, immediate early genes, neuronal signaling as well as neuronal growth and structure-associated genes, ipsilaterally (six genes) and/or contralaterally (eight genes in the motor and seven in the somatosensory cortex). In contrast, downregulations were restricted to ipsilateral areas and included genes coding for ion channels, transport proteins, mediators of metabolic pathways, and intracellular transducers (14 genes). A subset of these regulations were further confirmed by real-time polymerase chain reaction (TaqMan assay). At least part of the detected regulations, in particular those of the contralateral hemisphere, are likely to underlie plasticity processes.

[1]  P. Weinstein,et al.  Expression of Zinc Finger Immediate Early Genes in Rat Brain After Permanent Middle Cerebral Artery Occlusion , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  B R Rosen,et al.  A pilot study of somatotopic mapping after cortical infarct. , 2000, Stroke.

[3]  Eric R Kandel,et al.  CREB1 Encodes a Nuclear Activator, a Repressor, and a Cytoplasmic Modulator that Form a Regulatory Unit Critical for Long-Term Facilitation , 1998, Cell.

[4]  E. Schuman,et al.  Dendrites , 1978, Journal of the Geological Society.

[5]  H. Kondo,et al.  Localization of mRNA for protein phosphatase 2C in the brain of adult rats. , 1992, Brain research. Molecular brain research.

[6]  Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke. , 2000, Cerebrovascular diseases.

[7]  R. Busto,et al.  Induction of reproducible brain infarction by photochemically initiated thrombosis , 1985, Annals of neurology.

[8]  U. Certa,et al.  Parallel Gene Expression Monitoring using Oligonucleotide Probe Arrays of Multiple Transcripts with an Animal Model of Focal Ischemia , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  J. Baron,et al.  Cortical Hypometabolism and its Recovery following Nucleus Basalis Lesions in Baboons: A PET Study , 1987, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  O W Witte,et al.  Functional Differentiation of Multiple Perilesional Zones after Focal Cerebral Ischemia , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  T. Jones,et al.  Use-dependent growth of pyramidal neurons after neocortical damage , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  J. Sweatt,et al.  A necessity for MAP kinase activation in mammalian spatial learning. , 1999, Learning & memory.

[13]  R. Nudo,et al.  Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. , 1996, Journal of neurophysiology.

[14]  R. Malinow,et al.  Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. , 2000, Science.

[15]  J. Baron,et al.  Effects of thalamic stroke on energy metabolism of the cerebral cortex. A positron tomography study in man. , 1986, Brain : a journal of neurology.

[16]  K. Livak,et al.  Real time quantitative PCR. , 1996, Genome research.

[17]  Karl J. Zilles,et al.  The Cortex of the Rat: A Stereotaxic Atlas , 1985 .

[18]  J. Baron,et al.  Delayed Intrahemispheric Remote Hypometabolism , 2000, Cerebrovascular Diseases.

[19]  Hugo J. Bellen,et al.  Mutational analysis of Drosophila synaptotagmin demonstrates its essential role in Ca2+-activated neurotransmitter release , 1993, Cell.

[20]  T. Ono,et al.  Genomic Organization and Expression Pattern of Mouse Neuroglycan C in the Cerebellar Development* , 2000, The Journal of Biological Chemistry.

[21]  R. Fetter,et al.  Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons , 2000, Cell.

[22]  G. Kreutzberg,et al.  Regulation of MSCF receptors on microglia in the normal and injured mouse central nervous system: A quantitative immunofluorescence study using confocal laser microscopy , 1998, The Journal of comparative neurology.

[23]  E. Masliah,et al.  ALTERATIONS IN APOLIPOPROTEIN E EXPRESSION DURING AGING AND NEURODEGENERATION , 1996, Progress in Neurobiology.

[24]  E. Nagata,et al.  Immunohistochemical analysis of cyclic AMP response element binding protein phosphorylation in focal cerebral ischemia in rats , 1999, Brain Research.

[25]  O. Ohara,et al.  A novel RING-H2 motif protein downregulated by axotomy: its characteristic localization at the postsynaptic density of axosomatic synapse , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  J. Kleim,et al.  Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats: a quantitative electron microscopic examination , 1996, Brain Research.

[27]  I. Weiler,et al.  Correspondence between sites of NGFI-A induction and sites of morphological plasticity following exposure to environmental complexity. , 1995, Brain research. Molecular brain research.

[28]  A. Oohira,et al.  Neuroglycan C, a neural tissue-specific transmembrane chondroitin sulfate proteoglycan, in retinal neural network formation. , 2000, Investigative ophthalmology & visual science.

[29]  M. Nagao,et al.  Localization of mRNA for protein phosphatase 2A in the brain of adult rats. , 1992, Brain research. Molecular brain research.

[30]  N. Spruston,et al.  Prolonged Sodium Channel Inactivation Contributes to Dendritic Action Potential Attenuation in Hippocampal Pyramidal Neurons , 1997, The Journal of Neuroscience.

[31]  Alison L. Barth,et al.  Upregulation of cAMP Response Element-Mediated Gene Expression during Experience-Dependent Plasticity in Adult Neocortex , 2000, The Journal of Neuroscience.

[32]  J. D. McGaugh,et al.  Inhibition of Activity-Dependent Arc Protein Expression in the Rat Hippocampus Impairs the Maintenance of Long-Term Potentiation and the Consolidation of Long-Term Memory , 2000, The Journal of Neuroscience.

[33]  E. Rassart,et al.  Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion. , 1999, Brain research. Molecular brain research.

[34]  M. H. Cobb,et al.  Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3–CA1 synapses , 2000, Nature Neuroscience.

[35]  K Mizoi,et al.  Activation of Arc gene, a dendritic immediate early gene, by middle cerebral artery occlusion in rat brain. , 1999, Neuroreport.

[36]  C. Caltagirone,et al.  Hand motor cortical area reorganization in stroke: a study with fMRI, MEG and TCS maps , 1998, Neuroreport.

[37]  G. Tononi,et al.  Gene expression in the brain across the sleep–waking cycle 1 1 Published on the World Wide Web on 30 October 2000. , 2000, Brain Research.

[38]  A. Routtenberg,et al.  Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity. , 1996, Brain research. Molecular brain research.

[39]  Carol A Barnes,et al.  Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites , 1995, Neuron.

[40]  T. Südhof,et al.  A Phospho-Switch Controls the Dynamic Association of Synapsins with Synaptic Vesicles , 1999, Neuron.

[41]  R. Burke,et al.  Immediate early gene induction after neonatal hypoxia-ischemia. , 1993, Brain research. Molecular brain research.

[42]  G. Rougon,et al.  Regulated Expression of the Cell Adhesion Glycoprotein F3 in Adult Hypothalamic Magnocellular Neurons , 1998, The Journal of Neuroscience.

[43]  R. P. Stroemer,et al.  Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. , 1995, Stroke.

[44]  J. Seckl,et al.  Environmental influences on the central nervous system and their implications for the aging rat , 1993, Behavioural Brain Research.

[45]  Prof. Dr. Karl Zilles.  The Cortex of the Rat , 1985, Springer Berlin Heidelberg.

[46]  O. Witte,et al.  Suppression of proteasome C2 contralateral to ischemic lesions in rat brain , 2000, Brain Research.

[47]  Markus Missler,et al.  SV2A and SV2B Function as Redundant Ca2+ Regulators in Neurotransmitter Release , 1999, Neuron.