A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context

Etkin, Amit; Alarcón, Juan Marcos; Weisberg, Stuart P.; Touzani, Khalid; Huang, Yan; Nordheim, Alfred; Kandel, Eric R.

doi:10.1016/j.neuron.2006.03.013

Cited by 197 publications

(196 citation statements)

References 84 publications

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“…Furthermore, mice with lesions of the mPFC were able to master the nonmatching-to-position rule with the same rate as their control group did. There was no evidence of a lesion-induced deficit in locomotor activity, and similar findings were reported in two recent lesion studies (23,24). Taken together, these findings indicate that lesions of the mPFC did not compromise processing of attention or spatial information and did not produce a global learning, motivational, or motor deficit; rather, the lesions appear to affect specifically the ability of mice to learn the DNMTP task with proactive interference in the eight-arm radial maze.…”

Section: Discussionsupporting

confidence: 87%

Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex

Touzani

Puthanveettil²,

Kandel³

2007

Proc. Natl. Acad. Sci. U.S.A.

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Working memory is a temporary memory store where information is held briefly until the appropriate behavior is produced. However, the improvement in the performance of working memory tasks with practice over days points to the existence of a long-lasting component associated with learning strategies that lead to optimal performance. Here we show that the improvement in the performance of mice in a radial maze working memory task required the integrity of the medial prefrontal cortex (mPFC). We further demonstrate that this improvement of working memory performance requires the synthesis of de novo proteins in the mPFC. We suggest that in addition to storing memory briefly the mPFC is also involved in the consolidation and storage of the long-term learning strategies used in working memory.anisomycin ͉ mice ͉ prelimbic/infralimbic ͉ radial maze M ore than half a century ago, Hebb (1) proposed a dualtrace theory of memory in which he distinguished between short-term memory, a memory of recent events, and long-term memory, a memory of events that occurred in the past. Hebb proposed that the reverberating circuit of neuronal activity underlies short-term memory and that stabilization of this activity produces long-term memory. This dual-trace theory of memory found further support in the finding that inhibition of protein synthesis with antibiotics did not prevent the animals from learning tasks but disrupted their long-term memory (for example, see ref.2). It is now widely accepted that there are at least two stages of memory: (i) short-term memory that temporarily stores information on the basis of changes in preexisting connections due to covalent modifications of preexisting proteins (3) and (ii) long-term memory that stores this information more permanently through the growth of new connections as a result of transcription and translation of certain genes, a process called consolidation (4, 5). A specialized form of short-term memory, called ''working memory,'' was introduced by the cognitive psychologists Baddeley and Hitch (6) to describe the memory that temporarily stores information provided by an environmental cue for the execution of an act in the near term. According to Baddeley and Hitch (6), working memory is the cognitive process that allows moment-to-moment perceptions across time to be integrated, rehearsed, and combined with simultaneous access to archival information about past experience, actions, or knowledge.In primates and rodents, working memory is usually tested in a variety of moment-to-moment tasks in which sensory information is held in memory until a decision is made and the appropriate behavior is produced. However, a hallmark of working memory is that there is improvement in the performance of tasks over days with practice.

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Section: Discussionsupporting

confidence: 87%

Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex

Touzani

Puthanveettil²,

Kandel³

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings suggest a correlation between LTD and novelty detection during learning. Notably, LTD-null mice lacking serum response factor (SRF) failed to habituate to novel objects in an object-recognition task (44). It is interesting that SRF-knockout mice also display poor spatial memory in MWM, paralleling the presently observed effect of acute LTD blockade on spatial memory consolidation.…”

Section: Discussionmentioning

confidence: 90%

Hippocampal long-term depression is required for the consolidation of spatial memory

Dong

Bagot

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

256

204

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Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.hippocampus | learning and memory | long-term potentiation | AMPA receptor endocytosis | Morris water maze T he hippocampus plays crucial roles in encoding and consolidating memory (1, 2). Activity-dependent plasticity of hippocampal glutamatergic synapses, particularly NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and longterm depression (LTD), has been proposed as the primary cellular substrate for fulfilling these cognitive functions (3, 4). Indeed, formation of long-term spatial memory in the Morris water maze (MWM) can be impaired by preventing NMDAR activation using either pharmacological or genetic approaches (5-7). However, blocking NMDARs affects both LTP and LTD (8, 9), making it hard to attribute the observed spatial memory deficits to selective disruption of either LTP or LTD. Recent attempts using transgenic mice with deficits in either LTP (10-12) or LTD (13-15) have achieved some success in delineating the contribution of these two opposing forms of plasticity in memory formation. However, results obtained from transgenic studies are equivocal, perhaps because of structural alterations and/or functional compensatory changes at synapses that often arise after prolonged genetic alterations (14). Thus, determining the exact roles of hippocampal LTP and/or LTD in spatial memory requires new experimental approaches that enable acute, selective inhibition of LTP or LTD in freely moving animals.Evidence accumulated from recent studies suggests that GluN2A-and GluN2B-containing NMDARs preferentially contribute to the induction of hippocampal LTP and LTD in vitro (12,16,17) and in vivo (18). For example, the GluN2A preferential antagonist NVP-AAM077 (NVP) (19) and the GluN2B-specific antagonist Ro25-6981 (Ro) (20) selectively inhibit LTP and LTD, respectively, in anesthetized rats (18,21). If such GluN2 subunitselective requirements for LTP and LTD can be shown in freely moving ...

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“…Further evaluation of a forebrain SRF-knockout mouse model showed no change in the neuronal number; however, behavioral studies showed deficits in habituation to a novel spatial stimulus and defective memory and learning. 82 Microarray profiling of the hippocampi from this SRFknockout mouse showed attenuated expression of the genes involved in the release of calcium (eg, ryanodine receptors 1 and 3), although again, it is unclear whether these are direct or indirect SRF-target genes. 82 Alzheimer's disease (AD) is the most common form of dementia and represents, arguably, one of the most challenging ailments confronting the World Health Organization as no effective treatment exists to prevent or slow disease progression.…”

Section: Srf and Nervous System Disease Central Nervous Systemmentioning

confidence: 93%

“…82 Microarray profiling of the hippocampi from this SRFknockout mouse showed attenuated expression of the genes involved in the release of calcium (eg, ryanodine receptors 1 and 3), although again, it is unclear whether these are direct or indirect SRF-target genes. 82 Alzheimer's disease (AD) is the most common form of dementia and represents, arguably, one of the most challenging ailments confronting the World Health Organization as no effective treatment exists to prevent or slow disease progression. Furthermore, AD is very difficult to accurately diagnose in patients, and there is an expected sharp increase in the number of people who will acquire AD.…”

Section: Srf and Nervous System Disease Central Nervous Systemmentioning

confidence: 93%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

123

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context

Cited by 197 publications

References 84 publications

Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex

Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex

Hippocampal long-term depression is required for the consolidation of spatial memory

Role of serum response factor in the pathogenesis of disease

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