Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats (original) (raw)
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CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats
The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline. 1 of 23 RESEARCH ARTICLE 2013). The magnitude of this age-related decrease in neuronal excitability correlates with agerelated cognitive deficits . Aged impaired (AI) animals have larger AHPs than both young animals, and aged unimpaired (AU) animals. Interestingly, the AHP amplitude from AU animals is no different than that of young animals . Moreover, pharmacological compounds that reduce the amplitude of the AHP in vitro, ameliorate age-related cognitive impairments in vivo . Based on these findings, we are searching for molecular pathway(s) that modulate both cognition and intrinsic cellular excitability.
Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats
Brain Research, 2005
In the early process of long-term memory formation, cyclic AMP response element-binding protein (CREB), a transcription factor on which multiple signal transduction pathways converge, has been implicated. We examined whether the age difference in the performance of contextual fear conditioning (CFC) is associated with a change in activation of CREB in the hippocampus which is an important neural structure for long-term memory. The activation of CREB in the hippocampus in young (15 weeks old) and old (120 weeks old) male rats was determined immunohistochemically with an antibody that specifically recognizes the phosphorylated form of CREB (pCREB). Young rats exhibited better performance than old rats with respect to the freezing time in CFC. Phosphorylation of CREB as revealed by the ratio of the pCREB-immunoreactive cell number to the CREB-immunoreactive cell number was increased in the CA1 region, but not in other hippocampal regions following training for CFC. The close relationship between behavioral performance and CREB phosphorylation in the CA1 region suggests that hippocampal CREB is involved in age-related decline of learning and memory. D
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2001
At least two temporally and mechanistically distinct forms of memory are conserved across many species: short-term memory that persists minutes to hours after training and long-term memory (LTM) that persists days or longer. In general, repeated training trials presented with intervening rest intervals (spaced training) is more effective than massed training (the same number of training trials presented with no or short intervening rest intervals) in producing LTM. LTM requires de novo protein synthesis, and cAMP response element-binding protein (CREB) may be one of the transcription factors regulating the synthesis of new proteins necessary for the formation of LTM. Here we show that rats given massed fear conditioning training show no or weak LTM, as measured by fear-potentiated startle, compared with rats given the same amount of training but presented in a spaced manner. Increasing CREB levels specifically in the basolateral amygdala via viral vector-mediated gene transfer signi...
Cell, 1994
The cAMP-responsive element-binding protein (WEB) has been implicated in the activation of protein synthesis required for long-term facilitation, a cellular model of memory in Aplysia. Our studies with fear conditioning and with the water maze show that mice with a targeted disruption of the a and 6 isoforms of CREB are profoundly deficient in long-term memory. In contrast, short-term memory, lasting between 30 and 60 min, is normal. Consistent with models claiming a role for long-term potentiation (LTP) in memory, LTP in hippocampal slices from CREB mutants decayed to baseline 90 min after tetanic stimulation.
Hippocampus, 2005
In the present experiments, we used conditioned fear to study whether changes in expression or functional state of proteins known to be involved in hippocampal learning could suggest correlation with age-related memory deficits. We focused on both alterations constitutively present in the hippocampus of aged rats and alterations related to different learning responses. Our results point at the dysregulation of the phosphorylation state of CREB in the hippocampus of aged rats as a primary biochemical correlate of their impaired memory. Other proteins, known to be important for various steps of memory formation and consolidation and linked to CREB, are to some extent altered in their constitutive expression or in the response to learning in the aged hippocampus. In particular, phosphorylated CREB and Arc, a protein functionally related to CREB in memory consolidation, are both present at constitutively higher levels in the hippocampus of aged rats, but they are not susceptible to the learning-related up-regulation occurring in young adults. Two other CREB-regulated proteins involved in memory consolidation, the neurotrophin BDNF and the transcription factor C/EBPb, are expressed at similar levels in the hippocampus of young-adult and aged rats, but their response to conditioned fear learning appears dysregulated by aging. Calcineurin, a protein phosphatase having CREB among its substrates and whose expression negatively correlates with learning, is more expressed in the hippocampus of aged rats. However, while calcineurin expression decreases in the hippocampus of young adults after learning, no changes are observed in the hippocampus of aged, learning-impaired rats. V
Proceedings of the National Academy of Sciences, 1999
To study the physiological and molecular mechanisms of age-related memory loss, we assessed spatial memory in C57BL/B6 mice from different age cohorts and then measured in vitro the late phase of hippocampal longterm potentiation (L-LTP). Most young mice acquired the spatial task, whereas only a minority of aged mice did. Aged mice not only made significantly more errors but also exhibited greater individual differences. Slices from the hippocampus of aged mice exhibited significantly reduced L-LTP, and this was significantly and negatively correlated with errors in memory. Because L-LTP depends on cAMP activation, we examined whether drugs that enhanced cAMP would attenuate the L-LTP and memory defects. Both dopamine D1/D5 receptor agonists, which are positively coupled to adenylyl cyclase, and a cAMP phosphodiesterase inhibitor ameliorated the physiological as well as the memory defects, consistent with the idea that a cAMP-protein kinase A-dependent signaling pathway is defective in age-related spatial memory loss.
Hippocampus, 2009
Synaptic activity-dependent phosphorylation of the transcription factor cAMP response element binding protein (CREB) leads to CREB-dependent gene transcription, a process thought to underlie longterm hippocampal synaptic plasticity and memory formation. We previously reported that increasing CREB activity in glutamatergic neurons enhances synaptic plasticity and neuronal excitability. Whether these modifications are sufficient to promote hippocampal-dependent memory formation was not determined. Here, we provide direct evidence that a brief increase in CREB-dependent transcription in either CA1 or DG neurons, using in vivo viral vectors, is sufficient to boost memory for contextual representations, as tested in the contextual fear conditioning task, without affecting motor, pain, or anxiety behaviors. V V C 2008 Wiley-Liss, Inc.
Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice
Learning & Memory, 2004
We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinct pattern of age-related change, consisting mostly of gene overexpression in the middle-aged mice, suggesting that the induction of negative regulators in the middle-aged hippocampus could be involved in impairment of learning. Interestingly, we report changes in transcript levels for genes that could affect synaptic plasticity. Those changes could be involved in the memory deficits we observed in the 15-month-old mice. In agreement with previous reports, we also found altered expression in gene...
Proceedings of the National Academy of Sciences, 1997
Extensive evidence suggests that long term memory (LTM) formation is dependent on the activation of neuronal second messenger systems and requires protein synthesis. The cAMP response element binding protein (CREB) is a constitutively expressed regulatory transcription factor that couples changes in second messenger levels to changes in cellular transcription. Several recent studies suggest that CREB and related transcription factors regulate gene expression necessary for neuronal plasticity and LTM. However, the role of CREB, within defined mammalian brain structures, in mediating the cellular events underlying LTM formation has not been investigated. We examined whether CREB-mediated transcription within the dorsal hippocampus is critical to LTM consolidation of water maze spatial training, which is known to depend on dorsal hippocampal function. Pretraining infusions of antisense oligodeoxynucleotides (ODN) directed against CREB mRNA were used to disrupt hippocampal CREB protein levels in adult rats. Control groups received pretraining infusions of ODN of the same base composition but in a randomized order (scrambled ODN) or buffer. Task acquisition and memory up to 4 h (i.e., short term memory) were similar in CREB antisense ODN and control groups. In contrast, CREB antisense ODN-infused rats exhibited significantly impaired memory 48 h later (i.e., LTM). Moreover, administration of antisense ODN 1 day after training did not affect subsequent retention performance. These findings provide the first evidence that CREB-mediated transcription is integral to hippocampal-dependent memory consolidation 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 fact.
Rejuvenation Research, 2010
Microarray analysis was used to identify genes differentially expressed in the hippocampus of aged rats showing diverse long-term (3 and 6 h) spatial-associative memory performance in a single-trial inhibitory avoidance task. The transcription of 43 genes (including genes functionally linked to signal transduction, cell growth and differentiation, translation, energy metabolism, and nucleic acid processing) was significantly upregulated in good-versus bad-performing animals, whereas that of 18 genes (including genes functionally linked to transcription, cell growth and differentiation, apoptosis, and protein transport) was significantly downregulated in good-versus bad-performing animals. The differential expression of 14 of these genes was confirmed by realtime polymerase chain reaction.