Constitutive activation of CREB in mice enhances temporal association learning and increases hippocampal CA1 neuronal spine density and complexity

Tatsurou Serita,Hotaka Fukushima,Satoshi Kida

doi:10.1038/srep42528

Tatsurou Serita, Hotaka Fukushima + Show 1 more

Open Access

https://doi.org/10.1038/srep42528

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Abstract

Transcription factor CREB is believed to play essential roles in the formation of long-term memory (LTM), but not in learning and short-term memory (STM). Surprisingly, we previously showed that transgenic mice expressing a dominant active mutant of CREB (DIEDML) in the forebrain (DIEDML mice) demonstrated enhanced STM and LTM in hippocampal-dependent, rapid, one-trial learning tasks. Here we show that constitutive activation of CREB enhances hippocampal-dependent learning of temporal association in trace fear conditioning and delayed matching-to-place tasks. We then show that in DIEDML mice the apical tuft dendrites of hippocampal CA1 pyramidal neurons, required for temporal association learning, display increased spine density, especially of thin spines and of Homer1-negative spines. In contrast, the basal and apical oblique dendrites of CA1 neurons, required for rapid one-trial learning, show increased density of thin, stubby, and mushroom spines and of Homer1-positive spines. Furthermore, DIEDML mice showed increased dendritic complexity in the proximal portion of apical CA1 dendrites to the soma. In contrast, forebrain overexpression of CaMKIV, leading to enhanced LTM but not STM, show normal learning and CA1 neuron morphology. These findings suggest that dendritic region-specific morphological changes in CA1 neurons by constitutive activation of CREB may contribute to improved learning and STM.

Highlights

Short-term memory (STM) is in a labile state up to several hours after learning and is stabilized through memory consolidation, thereby becoming long-term memory (LTM)[1]
Consistent with previous observations, DIEDML mice showed enhanced LTM in the trace fear conditioning task. These observations suggest that constitutive activation of cAMP-responsive element-binding protein (CREB) improves temporal association learning as well as LTM
Previous studies suggested that hippocampus-dependent temporal association learning requires entorhinal cortex layer III (ECIII)-CA1 inputs to the apical tuft dendrites[35], whereas hippocampus-dependent rapid one-trial learning requires CA3-CA1 synaptic inputs to the basal and apical oblique dendrites, of hippocampal CA1 neurons[33,34,44]

Summary

Introduction

Short-term memory (STM) is in a labile state up to several hours after learning and is stabilized through memory consolidation, thereby becoming long-term memory (LTM)[1]. The loss of CREB or CaMKIV function disrupts memory consolidation; inhibition of CREB or CaMKIV function blocks the formation of LTM but does not impair STM3,6,7. The gain of CREB function by transgenic expression of wild type (wt) CaMKIV or a constitutively active CREB mutant (CREB DIEDML or Y134F) in the forebrain enhances LTM formation[8,9] These findings indicate that the CaMKIV-CREB signaling pathway functions as a positive regulator of LTM consolidation. Blocking the CaMKIV-CREB pathway inhibits dendritic outgrowth[22,23,24], whereas the acute expression of constitutively active CREB or wtCREB using a virus increased spine density in the hippocampal CA1 neurons of young adult rats and in principal neurons of the lateral amygdala in mice, respectively[25,26,27]. It is possible that CREB plays roles in neural connectivity and/or activity by regulating dendritic morphology or number

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