Reversible Inhibition of CREB/ATF Transcription Factors in Region CA1 of the Dorsal Hippocampus Disrupts Hippocampus-Dependent Spatial Memory

Abstract

CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB.

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

“…Given our results showing that TSA enhances memory for contextual fear via the transcription factor CREB, we next examined whether HDAC inhibition enhances LTP in hippocampal slices from CREB␣⌬ mutant mice. As mentioned previously, one-train E-LTP has been shown to be independent of CREB function (Pittenger et al, 2002) (for review, see Nguyen and Woo, 2003). Therefore, if disruption of CREB impairs the enhancement of LTP by HDAC inhibition, we can conclude that this is because the action of TSA is dependent on CREB and not because the disruption of CREB affects the underlying electrically induced E-LTP.…”

“…Here, we studied the effects of TSA on transient E-LTP induced by a single 1 s, 100 Hz train. Importantly, this form of LTP is independent of transcription or translation, protein kinase A, and CREB (for review, see Pittenger et al, 2002;Nguyen and Woo, 2003). Therefore, this approach allows us to identify genetic and pharmacological manipulations that selectively disrupt the enhancement in LTP attributable to TSA treatment without affecting the underlying E-LTP.…”

“…The transcription factor CREB is thought to activate transcription through the coactivator CBP and its associated HAT activity (for review, see Goodman and Smolik, 2000), and the significant phenotypic overlap between memory and synaptic plasticity deficits attributable to genetic disruption of CREB or CBP suggests that they function together during memory processes (Pittenger et al, 2002;Josselyn, 2005;Wood et al, 2005). Given this potential modulation of CREB-mediated transcription by histone acetylation, we hypothesized that CREB might have a role in the enhancement of memory and E-LTP after HDAC inhibition.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Moreover, injection of the JNK inhibitor SP600125 into the mouse hippocampus reduces long-term memory [146]. On the other hand, expression of a dominant-negative form of CREB, which blocks the activity of all CREB heterodimers, disrupts hippocampus-dependent spatial memory [147]. Moreover, hippocampal granule cell proliferation is increased by activation of cAMP signaling and reduced by CREB inhibition [148], and combined disruption of CREB and CREM leads to neurodegeneration in the hippocampus and in the dorsolateral striatum [121].…”

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

“…Post hoc analysis using Bonferroni correction indicates that the AAV‐ShRNATau mice were significantly impaired on Day 5 of the learning trial as evident by both an increased latency to the platform ( p  <   .01) and distance traveled to the platform location ( p  <   .01). Even though it may seem unusual that a group of mice is statistically different from another only during the last day of training, other groups have reported similar findings (e.g., Darcet et al., 2014; Pittenger et al., 2002; Sun et al., 2014). On Day 6, we removed the platform and tested the mice in a 60‐s probe trial, to assess spatial memory.…”