Somatodendritic expression of an immediate early gene is regulated by synaptic activity.

Abstract

Trans-synaptic activation of gene expression is linked to long-term plastic adaptations in the nervous system. To examine the molecular program induced by synaptic activity, we have employed molecular cloning techniques to identify an immediate early gene that is rapidly induced in the brain. We here report the entire nucleotide sequence of the cDNA, which encodes an open reading frame of 396 amino acids. Within the hippocampus, constitutive expression was low. Basal levels of expression in the cortex were high but can be markedly reduced by blockade of N-methyl-D-aspartate receptors. By contrast, synaptic activity induced by convulsive seizures increased mRNA levels in neurons of the cortex and hippocampus. High-frequency stimulation of the perforant path resulted in long-term potentiation and a spatially confined dramatic increase in the level of mRNA in the granule cells of the ipsilateral dentate gyrus. Transcripts were localized to the soma and to the dendrites of the granule cells. The dendritic localization of the transcripts offers the potential for local synthesis of the protein at activated postsynaptic sites and may underlie synapse-specific modifications during longterm plastic events.Activity-dependent alterations of neuronal connectivity are characteristic of plastic events in the nervous system. Plasticity is associated with physiological processes such as learning and memory as well as neuropathological states, including epilepsy. Seizure episodes set in motion a cascade of events that include gene expression, sprouting of fibers, and the establishment of new synaptic contacts (1). These long-lasting alterations are reminiscent of changes that occur during long-term potentiation (LTP) of synaptic transmission in the mammalian brain. LTP is an activity-dependent and persistent enhancement of synaptic efficacy that may underlie certain forms of long-term memory (2, 3). In both invertebrates and vertebrates, longterm memory differs from short-term memory in that it requires RNA and protein synthesis (4, 5). As is the case for memory in the intact animal, LTP is blocked by inhibitors of RNA and protein synthesis (6-9). Attention therefore has been focused on identifying activity-induced genes. In invertebrates, behavioral training elicits changes in the level of specific mRNAs in cells involved in learning (10, 11). In mammalian brain and spinal chord neurons, a variety of physiological and pathological stimuli induce rapid and transient activation of immediate early genes (IEGs) (12). Many of the IEGs encode transcription factors that may control the expression of downstream effector genes (13-15). More recent studies have identified genes that may themselves have effector function with the potential to quickly promote long-term alterations in neuronal phenotype during plastic processes, The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fac...

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…Previous studies have established that the expression of Arc is activated by neuronal activity (1,2,4,5). Consistent with this finding, we found that the expression of Arc mRNA was also increased by the direct activation of NMDA receptor (NMDAR) with exogenously added NMDA (Fig.…”

“…The gene encoding activity-regulated cytoskeleton-associated protein (Arc), 3 also known as the activity-regulated gene of 3.1 kb (Arg3.1), is an immediate early gene (IEG), the expression of which is rapidly activated in response to neuronal activity (1,2). In neurons, Arc expression is regulated by various stimuli including not only neuronal activity, but also BDNF, cAMP, and PDGF (3)(4)(5)(6).…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…Fos and Zif/268 are nuclear transcription factors that regulate the expression of late-target genes whereas the protein products of the effector genes, arc and bdnf, are rapidly expressed and delivered to activated synapses (Link et al 1995;Steward and Worley 2001;Ying et al 2002;Bozon et al 2003;Tongiorgi et al 2004). In addition, early phases of instrumental learning (Hernandez et al 2006;Kelly and Deadwyler 2003) elicit widespread zif/268 and arc induction throughout an extensive corticostriatal network in rats, whereas manipulation of BDNF levels in the brain alters cocaine-seeking in a regionally selective manner (Horger et al 1999;Lu et al 2004;Berglind et al 2007;Graham et al 2007).…”

RNA Transport in Dendrites: Acis-Acting Targeting Element Is Contained within Neuronal BC1 RNA

“…The hypothesis of dendritic translation has been strengthened in recent years by the discovery in dendrites of various types of mRNAs and nonmessenger RNAs. Dendritic mRNAs include, among others, those encoding: (1) the high molecular mass forms of microtubule-associated protein 2 (MAP2a / b; Garner et al, 1988;Bruckenstein et al, 1990;Kleiman et al, 1990), (2) the ␣-subunit of Ca 2ϩ /calmodulin-dependent protein kinase type II (CaMKII␣; Burgin et al, 1990); (3) the inositol 1,4,5-trisphosphate receptor type 1 (InsP 3 R1; Furuichi et al, 1993); (4) neurogranin (Ng / RC3; Landry et al, 1994); (5) a number of amino acid receptor subunits (Miyashiro et al, 1994;Racca et al, 1997); and (6) the cytoskeleton-associated protein Arc (Link et al, 1995;Lyford et al, 1995). Dendritic nonmessenger RNAs include BC1 RNA , ribosomal RNAs (rRNAs) (Kleiman et al, 1993;1994), and tRNAs .…”