Neuron-specific enolase-cre mouse line with cre activity in specific neuronal populations

Kwon, Chil Hun; Zhou, Jing; Li, Yanjiao; Kim, Ki Woo; Hensley, Lori L.; Baker, Suzanne J.; Parada, Luis F.

doi:10.1002/gene.20197

Cited by 45 publications

(49 citation statements)

References 17 publications

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“…Thus, in the hippocampus of this mouse with Cre under the Nse promoter, Pten was lost primarily in DGCs and CA3 pyramidal neurons. Neurons of origin of perforant path afferents in layer II of the entorhinal cortex (23) show minimal Cre expression (24) and presumably express normal levels of Pten.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

Takeuchi

Gertner

Zhou

et al. 2013

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

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114

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The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase-and protein synthesis-dependent forms of synaptic plasticity, theta burstinduced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young NseCre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.T he discovery of genes associated with autism spectrum disorders (ASDs) has largely depended on gene linkage analyses within lineages of humans with familial ASDs (1-3). A well-established candidate gene is the tumor-suppressor gene, phosphatase and tensin homolog missing on chromosome 10 (PTEN) (4-7). Pten is a lipid and protein phosphatase best known for its role in suppressing tumor formation by inhibiting cellular survival, proliferation, and cellular architecture (8, 9), but which also plays an important role in brain morphology and synaptic function (10, 11). Pten acts via its lipid phosphatase activity to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate and negatively regulate the PI3K-mammalian target of rapamycin (mTOR) signaling pathway. Although PTEN mutations are present in 5-10% of people with ASDs (12-14), loss-of-function point mutations in this gene give rise to progressive macrocephaly, a hallmark feature that occurs in nearly 20% of humans with ASDs (5, 6). In addition to anatomical abnormalities, humans with inactivating PTEN mutations exhibit spontaneous seizures and deficits in social and cognitive behaviors (10, 11).A conditional Pten knockout mouse (cKO) in which both alleles of the Pten gene contain loxP sites and Cre recombinase (Cre) is expressed under the neuron-specific enolase promoter (Nse-Cre) provides a clinically relevant mouse model for humans with inactivating PTEN mutations (15). In Nse-Cre Pten cKO (hereafter P...

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Section: Resultsmentioning

confidence: 99%

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

Takeuchi

Gertner

Zhou

et al. 2013

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

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114

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“…To examine whether MEF2 is sufficient to restrain excitatory synapse number in vivo, we expressed a superactive MEF2C-VP16 protein under the control of the rat neuron-specific enolase (NSE) promoter/enhancer, which begins to be expressed shortly after the initiation of synaptogenesis in discrete mature neuronal populations in the cerebral cortex and hippocampus (22). Expression of MEF2C-VP16 was confirmed by in situ hybridization to be confined to subsets of differentiated neurons, mostly in layers III-V of the cerebral cortex and in the CA3, dentate gyrus granular layer (GL), and polymorphic layer (PML) of the hippocampus (Fig.…”

Section: Mef2c-vp16 Suppresses Excitatory Synapse Number In Vivo Withoutmentioning

confidence: 99%

MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function

Barbosa¹,

Kim²,

Ertunç

et al. 2008

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

255

304

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Learning and memory depend on the activity-dependent structural plasticity of synapses and changes in neuronal gene expression. We show that deletion of the MEF2C transcription factor in the CNS of mice impairs hippocampal-dependent learning and memory. Unexpectedly, these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission. Conversely, neuronal expression of a superactivating form of MEF2C results in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. We conclude that MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampaldependent learning and memory.synaptic transmission ͉ synaptogenesis ͉ learning deficits N eurons process and retain information by forming synaptic connections that are modified by the intensity and frequency of their activity. The capacity to regulate the efficacy of synaptic transmission is essential for the continual remodeling of neural networks required for cognitive processes such as learning and memory. Distinct molecular mechanisms control synaptic plasticity associated with the different temporal stages of memory. A short-term process lasting minutes depends on modifications of preexisting proteins, whereas a long-term process lasting hours and days depends on changes in gene expression and protein synthesis (1).Originally identified as regulators of muscle development, members of the MEF2 (Myocyte Enhancer Factor 2) family of MADS (MCM1, agamous, deficiens, serum response factor) box transcription factors are expressed in overlapping but distinct regions of the CNS that correlate with the withdrawal of neurons from the cell cycle and acquisition of a differentiated phenotype (2). Mef2c is the first of four Mef2 genes to be expressed in the CNS and, in the adult brain, is highly expressed in the frontal cortex, entorhinal cortex, dentate gyrus, and amygdala (3, 4). RNA interference-mediated knockdown of MEF2A and MEF2D in cultured hippocampal neurons increases the number of excitatory synapses and the frequency of miniature excitatory postsynaptic currents (mEPSCs) (5). These alterations depend on the ability of the MEF2 proteins to stimulate neural activitydependent transcription of target genes (5). In contrast, loss of MEF2A in cerebellar granule neurons results in a decrease in the number of dendritic claws (6).Here, we present an analysis of the neuronal functions of the Mef2 gene in vivo. Through conditional deletion of Mef2c and expression of a superactive form of MEF2C in neurons of mice, we show that this MEF2 isoform plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. ResultsBrain-Specific Deletion of MEF2C. We deleted Mef2c specifically in the CNS by breeding Mef2c loxP/loxP females (7) to Mef2c KO/ϩ heterozygous male (8) mice h...

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“…At the level of the whole brain, cell-specific promoters can be used to target Cre recombinase expression to specific cell types (i.e., neurons or glia). Although our ability to target specific populations of neurons has improved (44,45), examining regional angiotensinergic pathways has become more difficult, as promoters that have the ability to target specific regions of the brain, such as the SFO or MnPO, have yet to be identified. Certainly will be one of the long-anticipated outcomes of the brain genome and mapping projects (46).…”

Section: Figurementioning

confidence: 99%

Local production of angiotensin II in the subfornical organ causes elevated drinking

Sakai¹,

Agassandian²,

Morimoto³

et al. 2007

J. Clin. Invest.

143

139

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. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II-like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGT flox ), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT flox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA flox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.

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Neuron-specific enolase-cre mouse line with cre activity in specific neuronal populations

Cited by 45 publications

References 17 publications

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function

Local production of angiotensin II in the subfornical organ causes elevated drinking

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