Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity

Pulipparacharuvil, Suprabha; Renthal, William; Hale, Carly F.; Taniguchi, Makoto; Xiao, Guanghua; Kumar, Arvind; Russo, Scott J.; Sikder, Devanjan; Dewey, Colleen M.; Davis, Maya M.; Greengard, Paul; Nairn, Angus C.; Nestler, Eric J.; Cowan, Christopher W.

doi:10.1016/j.neuron.2008.06.020

Cited by 252 publications

(286 citation statements)

References 40 publications

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“…S6). This indicates that increasing MEF2-dependent transcription does not simply suppress or eliminate spines under basal conditions (15,16). The dissociable effects of increasing MEF2 function on spine density support the idea that MEF2 regulates reactivation-driven changes in spine density within a defined posttraining window.…”

Section: Resultsmentioning

confidence: 66%

“…For example, increasing MEF2 function decreases the number of dendritic spines and excitatory synapses in vitro (15) and blocks increases in spine density normally observed following repeated cocaine administration in rat medium spiny nucleus accumbens neurons in vivo (16). Accordingly, in our experiments, we used a viral vector-based strategy to increase MEF2 function in the aCC at specific times following contextual fear conditioning.…”

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confidence: 99%

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Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

Vetere

Restivo

Cole

et al. 2011

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

160

135

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Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation-associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical structural remodeling and memory consolidation and, further, identify MEF2 as a key regulator of these processes.structural plasticity | remote memory | viral vector I n experimental animals, damage to the hippocampus disproportionately impacts recently acquired memories, with relative sparing of remote memories (1-8). Such observations have led to the idea that the hippocampus is transiently required for memory expression, with remote memory expression being exclusively dependent on the cortex (9). According to one model (10), posttraining hippocampal activity coordinates reactivation of memory traces in the cortex. This reactivation leads to the remodeling of cortical connections, allowing the memory to eventually be expressed independently of the hippocampus. A recent study in mice (5) provided correlative evidence for posttraining remodeling of neurons in the anterior cingulate cortex (aCC), a subregion of the prefrontal cortex that plays an essential role in remote memory expression (11). Increases in dendritic spine density on layer 2/3 pyramidal aCC neurons were observed 1 mo, but not 1 d, following contextual fear conditioning (5). As layer 2/3 pyramidal neurons send and receive long-range cortical connections (12), such changes may contribute to increased functional connectivity between the aCC and other cortical areas important for remote memory expression (13,14). However, whether this increase in aCC spine density is necessary for memory consolidation is not known. To test this, it would be necessary to evaluate whether preventing posttraining spinogenesis, specifically in this region, disrupts memory consolidation.The transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis in an activity-dependent manner and therefore provides a tool to address this question. For example, increasing MEF2 function decreases the number of dendritic spines and excitatory synapses in vitro (15) and blocks increases in spine density normally observed following repeated cocaine administration in rat medium spiny...

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Section: Resultsmentioning

confidence: 66%

mentioning

confidence: 99%

Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

Vetere

Restivo

Cole

et al. 2011

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

160

135

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“…( known regulators of activity-dependent synaptic development programs, such as MEF2A (Lyons et al 1995;Flavell et al 2006;Shalizi et al 2006). MEF2A plays multiple roles in neuronal development, including neuronal survival (Mao et al 1999;Shalizi et al 2003), dendritic differentiation (Shalizi et al 2006), synaptic density of hippocampal neurons (Flavell et al 2006;Barbosa et al 2008), spine density in nucleus accumbens (Pulipparacharuvil et al 2008), and both synapse weakening/elimination and synaptic strengthening (Flavell et al 2008). In our data, expression profiles that correlated with MEF2A include predicted reported MEF2A target genes associated with both synaptic weakening (e.g., ARC, SYNGAP1, and NR4A1) and synaptic strengthening (e.g., BDNF, LGI1).…”

Section: Discussionmentioning

confidence: 99%

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

Liu¹,

Somel²,

Tang³

et al. 2012

Genome Res.

216

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Over the course of ontogenesis, the human brain and human cognitive abilities develop in parallel, resulting in a phenotype strikingly distinct from that of other primates. Here, we used microarrays and RNA-sequencing to examine human-specific gene expression changes taking place during postnatal brain development in the prefrontal cortex and cerebellum of humans, chimpanzees, and rhesus macaques. We show that the most prominent human-specific expression change affects genes associated with synaptic functions and represents an extreme shift in the timing of synaptic development in the prefrontal cortex, but not the cerebellum. Consequently, peak expression of synaptic genes in the prefrontal cortex is shifted from <1 yr in chimpanzees and macaques to 5 yr in humans. This result was supported by protein expression profiles of synaptic density markers and by direct observation of synaptic density by electron microscopy. Mechanistically, the human-specific change in timing of synaptic development involves the MEF2A-mediated activity-dependent regulatory pathway. Evolutionarily, this change may have taken place after the split of the human and the Neanderthal lineages.

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“…Furthermore, like FoxO6 mutant mice, mice deficient for Mef2c have defects in contextual memory (Barbosa et al 2008). However, in contrast to FoxO6, the MEF2 family of transcription factors negatively regulates synapse number (Flavell et al 2006;Barbosa et al 2008;Pulipparacharuvil et al 2008). Thus, it is possible that FoxO6 and MEF2 share similar subsets of genes, but that these transcription factors regulate genes in an opposing manner or a different time frame.…”

Section: Foxo6 Regulates a Gene Expression Program Involved In Synapsmentioning

confidence: 99%

“…For example, the activitydependent transcription factor CREB plays an important role in regulating a gene expression program important for synaptic function (Tao et al 1998), synaptic plasticity (Barco et al 2002), and reward and addiction behaviors (Carlezon et al 1998;Larson et al 2011). Furthermore, MEF2, another activity-dependent transcription factor, is important for synaptic function (Flavell et al 2006;Shalizi et al 2006), learning and memory (Barbosa et al 2008), and behavioral plasticity in response to drugs of abuse (Pulipparacharuvil et al 2008). Several additional transcriptional regulators, including histone acetylases and deacetylases (Alarcon et al 2004;Fischer et al 2007;Peleg et al 2010), histone methyltransferases (Maze et al 2010;Covington et al 2011), and chromatin-binding proteins like MeCP2 (Moretti et al 2006;Zhou et al 2006;Chahrour et al 2008;Deng et al 2010;Cohen et al 2011;Goffin et al 2012), also play an essential role in the regulation of gene expression, synaptic plasticity, and cognitive behaviors.…”

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confidence: 99%

FoxO6 regulates memory consolidation and synaptic function

et al. 2012

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The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

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Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity

Cited by 252 publications

References 40 publications

Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques

FoxO6 regulates memory consolidation and synaptic function

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