Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory

L Wieczorek,D Majumdar,T A Wills,D G Winder,L J Muglia,L Hu,D J Webb

doi:10.1038/tp.2012.50

L Wieczorek, D Majumdar + Show 5 more

Open Access

PDF Available

https://doi.org/10.1038/tp.2012.50

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Ca2+-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca2+ increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca2+-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca2+-stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double-knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca2+-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene–environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience-dependent changes in CF memory. We showed that the strength of CF memory in wild-type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory.

Highlights

The Ca2 þ -stimulated adenylyl cyclase (AC) pathway couples neuronal activity and intracellular Ca2 þ increases to the production of cyclic adenosine monophosphate
PKA is activated by Ca2 þ -stimulated AC-mediated binding of cyclic adenosine monophosphate,[9] and initial activation of Ca2 þ -stimulated ACs may be necessary for environmental-dependent changes in fear memory
To examine if Ca2 þ -stimulated AC activity modulates the abundance and distribution of synaptic vesicle protein 2 (SV2) along the dendritic processes, we first measured the number of SV2 clusters as well as the average SV2 cluster size in vitro, in hippocampal cultures from WT and DKO mice

Summary

Introduction

The Ca2 þ -stimulated adenylyl cyclase (AC) pathway couples neuronal activity and intracellular Ca2 þ increases to the production of cyclic adenosine monophosphate Through this activity-dependent increase in cyclic adenosine monophosphate, the Ca2 þ -stimulated ACs, AC1 and AC8, are able to significantly modulate processes that are defined by marked changes in synaptic plasticity, memory, and long-term potentiation (LTP). This is evident on a variety of learning paradigms where AC1/AC8 double-knockout (DKO) mice showed memory impairments, such as passive avoidance,[1] conditioned fear (CF),[1,2] and novel object recognition.[2,3] Schaeffer collateral-CA1 LTP is impaired in DKO mice,[1,4] while mossy fiber LTP is impaired in AC15 or AC86 single-knockout mice. Environmental enrichment increases the expression of synaptic proteins, such as synaptophysin and postsynaptic density-9511,12 as well as overall synaptic strength as evident by increases in LTP.[8,13,14,15] Neurogenesis, the other major process shown to mediate experiencedependent changes in memory, is increased after environmental enrichment.[16,17,18]

Methods

Results

Conclusion