Egr3, a synaptic activity regulated transcription factor that is essential for learning and memory

Learning and memory depend upon poorly defined synaptic and intracellular modifications that occur in activated neurons. Mitogen activated protein kinase-extracellular regulated kinase (MAPK-ERK) signaling and de novo protein synthesis are essential aspects of enduring memory formation, but the precise effector molecules of MAPK-ERK signaling in neurons are not well defined. Early growth response (Egr) transcriptional regulators are examples of MAPK-ERK regulated genes and Egr1 (zif268) has been widely recognized as essential for some aspects of learning and memory. Here we show that Egr3, a transcriptional regulator closely related to Egr1, is essential for normal hippocampal long-term potentiation (LTP) and for hippocampal and amygdala dependent learning and memory. In the absence of Egr3, the defects in learning and memory appear to be independent of Egr1 since Egr1 protein levels are not altered in amygdala, hippocampus or cortex. Moreover, unlike Egr1-deficient mice which have impairments in late phase hippocampal LTP and consolidation of some forms of long-term hippocampus- and amygdala-dependent memory, Egr3-deficient mice have profound defects in early- and late-phase hippocampal LTP, as well as short-term and long-term hippocampus- and amygdala-dependent learning and memory. Thus, Egr3 has an essential role in learning and memory processing that appears to be partly distinct from the role of Egr1.

[1]  T. Bliss,et al.  A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories , 2001, Nature Neuroscience.

[2]  J. Baraban,et al.  The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience , 1999, Trends in Neurosciences.

[3]  S Schoch,et al.  The Human Synapsin II Gene Promoter , 1995, The Journal of Biological Chemistry.

[4]  S. Davis,et al.  The MAPK/ERK Cascade Targets Both Elk-1 and cAMP Response Element-Binding Protein to Control Long-Term Potentiation-Dependent Gene Expression in the Dentate Gyrus In Vivo , 2000, The Journal of Neuroscience.

[5]  U. Frey,et al.  Somatodendritic expression of an immediate early gene is regulated by synaptic activity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Andrew J. Cole,et al.  Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation , 1989, Nature.

[7]  F. Sharp,et al.  Prolonged expression of zinc finger immediate‐early gene mRNAs and decreased protein synthesis following kainic acid induced seizures , 1999, The European journal of neuroscience.

[8]  Joseph E LeDoux,et al.  Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. , 1992, Behavioral neuroscience.

[9]  J. Milbrandt,et al.  DNA-binding specificity of NGFI-A and related zinc finger transcription factors , 1995, Molecular and cellular biology.

[10]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[11]  C. Keller-Peck,et al.  Glial cell-line derived neurotrophic factor-dependent fusimotor neuron survival during development , 2005, Mechanisms of Development.

[12]  S Schoch,et al.  Regulation of synapsin I gene expression by the zinc finger transcription factor zif268/egr-1. , 1994, The Journal of biological chemistry.

[13]  S. Schneider-Maunoury,et al.  Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice. , 1998, Molecular endocrinology.

[14]  R. Huganir,et al.  MAPK cascade signalling and synaptic plasticity , 2004, Nature Reviews Neuroscience.

[15]  J. Milbrandt,et al.  Luteinizing Hormone Deficiency and Female Infertility in Mice Lacking the Transcription Factor NGFI-A (Egr-1) , 1996, Science.

[16]  J. David Sweatt,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation* , 1997, The Journal of Biological Chemistry.

[17]  W. Tourtellotte,et al.  The Neuroplasticity-Associated Arc Gene Is a Direct Transcriptional Target of Early Growth Response (Egr) Transcription Factors , 2005, Molecular and Cellular Biology.

[18]  J. Baraban,et al.  Major Egr3 Isoforms Are Generated via Alternate Translation Start Sites and Differ in Their Abilities To Activate Transcription , 1999, Molecular and Cellular Biology.

[19]  P. Dash,et al.  A Mitogen-Activated Protein Kinase Cascade in the CA1/CA2 Subfield of the Dorsal Hippocampus Is Essential for Long-Term Spatial Memory , 1999, The Journal of Neuroscience.

[20]  A. Brooks-Kayal,et al.  Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Robert E. Clark,et al.  Impaired Recognition Memory in Rats after Damage to the Hippocampus , 2000, The Journal of Neuroscience.

[22]  Edwin J. Weeber,et al.  A Role for the β Isoform of Protein Kinase C in Fear Conditioning , 2000, The Journal of Neuroscience.

[23]  R. Clark,et al.  Impaired Recognition Memory in Monkeys after Damage Limited to the Hippocampal Region , 2000, The Journal of Neuroscience.

[24]  M. Segal.  Dendritic spines and long-term plasticity , 2005, Nature Reviews Neuroscience.

[25]  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.

[26]  J. Radulovic,et al.  Generalization of fear responses in C57BL/6N mice subjected to one-trial foreground contextual fear conditioning , 1998, Behavioural Brain Research.

[27]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[28]  B. Everitt,et al.  Independent Cellular Processes for Hippocampal Memory Consolidation and Reconsolidation , 2004, Science.

[29]  T. Bliss,et al.  ERKI/II Regulation by the Muscarinic Acetylcholine Receptors in Neurons , 2000, The Journal of Neuroscience.

[30]  E. Kandel,et al.  Cognitive Neuroscience and the Study of Memory , 1998, Neuron.

[31]  C. Keller-Peck,et al.  The transcription factor Egr3 modulates sensory axon-myotube interactions during muscle spindle morphogenesis. , 2001, Developmental biology.

[32]  J. David Sweatt,et al.  The MAPK cascade is required for mammalian associative learning , 1998, Nature Neuroscience.

[33]  M. Zhuo,et al.  Transcription factor Egr-1 is required for long-term fear memory and anxiety. , 2005, Sheng li xue bao : [Acta physiologica Sinica].

[34]  A. Coogan,et al.  P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro. , 1999, Journal of neurophysiology.

[35]  C A Barnes,et al.  Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. , 1994, Learning & memory.

[36]  B. Trommer,et al.  Blockade of nicotinic acetylcholine receptors suppresses hippocampal long‐term potentiation in wild‐type but not ApoE4 targeted replacement mice , 2005, Journal of neuroscience research.

[37]  Bruno Bozon,et al.  A Requirement for the Immediate Early Gene zif268 in Reconsolidation of Recognition Memory after Retrieval , 2003, Neuron.

[38]  Alcino J. Silva,et al.  Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein , 1994, Cell.

[39]  H. Xiong,et al.  Human immunodeficiency virus type 1 gp120 inhibits long‐term potentiation via chemokine receptor CXCR4 in rat hippocampal slices , 2006, Journal of neuroscience research.

[40]  J. Milbrandt,et al.  Functional Compensation by Egr4 inEgr1-Dependent Luteinizing Hormone Regulation and Leydig Cell Steroidogenesis , 2000, Molecular and Cellular Biology.

[41]  M. Fanselow,et al.  Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. , 1993, Behavioral neuroscience.

[42]  J. Milbrandt,et al.  Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3 , 1998, Nature Genetics.

[43]  J. David Sweatt,et al.  Activation of p42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation* , 1996, The Journal of Biological Chemistry.