Epac activation initiates associative odor preference memories in the rat pup

Grimes, Matthew T.; Powell, Maria; Gutierrez, Sandra Mohammed; Darby‐King, Andrea; Harley, Carolyn W.; McLean, John H.

doi:10.1101/lm.037101.114

Cited by 15 publications

(18 citation statements)

References 83 publications

(101 reference statements)

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“…Thus, tubacin does not induce a generalized odor preference to normally aversive odors. We previously showed pups have the ability to show preference to the normally aversive orange odor if they are trained in the presence of orange odor (Grimes et al 2015). This, and the present findings, suggests tubacin-enhanced odor preference memory is specific to the paired odor.…”

Section: An Hdac 6 Inhibitor Extends Memory and Is Specific To The Cosupporting

confidence: 82%

Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model

et al. 2017

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Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24-h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d. The prolonged odor preference memory was selective for the paired odor and was also observed using a specific HDAC6 inhibitor, tubacin, supporting a role for histone acetylation in associative memory. Immunoblot analysis showed that GluA1 receptor membrane expression in the olfactory bulbs of the TSA-treated group was significantly increased at 48 h unlike control rats without TSA. Immunohistochemistry revealed significant increase of GluA1 expression in olfactory bulb glomeruli 5 d after training. These results extend previous evidence for a close relationship between enhanced GluA1 receptor membrane expression and memory expression. Together, these findings provide a new single-trial appetitive model for understanding the support and maintenance of memories of varying duration.

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Section: An Hdac 6 Inhibitor Extends Memory and Is Specific To The Cosupporting

confidence: 82%

Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model

et al. 2017

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“…Stimulation of hippocampal slices with an EPAC agonist leads to increased LTP stability and activation of ERK (343,514). A similar formation of preferential long-term odor memory in rats was observed to be enhanced by the activation of an EPAC/ERK pathway (370). Another study also concluded that loss of EPAC2 could impair LTD in the hippocampus and illustrated a moderate reduction in learning behaviors in these animals (590).…”

Section: Behaviormentioning

confidence: 71%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

153

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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“…Nonetheless, the currently sparse literature on Epac and memory processing supports the notion that Epac has key roles in memory dynamics. Epac activation can modulate associative odor memories in rat pups (Grimes et al 2015), and Epac signaling is critical for hippocampal memory retrieval (Ouyang et al 2008;Ostroveanu et al 2010). Conversely, Epac activation in the amygdala impeded cocaine-induced memory reconsolidation (Wan et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Noradrenergic stabilization of heterosynaptic LTP requires activation of Epac in the hippocampus

Brandwein

Nguyen

2019

Learn. Mem.

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Beta-adrenergic receptor (β-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that β-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after β-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation ("NE-LTP"). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo-and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo-and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.

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Epac activation initiates associative odor preference memories in the rat pup

Cited by 15 publications

References 83 publications

Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model

Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Noradrenergic stabilization of heterosynaptic LTP requires activation of Epac in the hippocampus

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