The Role of β-Catenin in Long-Term Memory Formation Público
Maguschak, Kimberly Ann (2010)
Abstract
Abstract
The Role of β-Catenin in Long-Term Memory Formation
By Kimberly A. Maguschak
The ability of connections between neurons to change as a function
of learning is commonly referred to as synaptic plasticity. Such
changes in synaptic morphology and organization are thought to
underpin long term memory formation. Among the most studied
structural changes has been the elaboration of new synaptic
architecture following a learning event. This process has been
postulated by many investigators to be a physiologically-relevant
means of synaptic potentiation. The processes governing dendritic
morphogenesis are many and varied, but much work has focused on the
role of β-catenin in allowing the remodeling of synapses in an
activity-dependent way. β-Catenin is expressed broadly in the
adult mammalian brain and plays a role in both cadherin-mediated
cell-cell adhesion and Wnt signaling. Although β-catenin has
been implicated in neuronal synapse regulation and plasticity, all
of this work has been done in vitro, and not in intact
animals. Here we have examined the role of β-catenin in the
adult mouse brain and its role in amygdala- and
hippocampal-dependent learning and memory. We found that
β-catenin is highly expressed in these brain regions and is
dynamically regulated at the post-translational level with fear
learning. Such alterations correlated with a change in the
association of β-catenin with cadherin. Genetically, the role
of β-catenin was confirmed with site-specific deletions of
loxP-flanked Ctnnb1 (encoding β-catenin) in the
amygdala or dorsal hippocampus. In both cases, the manipulation
affected the consolidation, but not acquisition, of memory.
Notably, Ctnnb1 deletion did not affect a number of other
behaviors, including locomotor or anxiety-related behavior.
Furthermore, we found that Wnt signaling may play a role in
mediating β-catenin dependent memory formation. Interfering
with Wnt signaling prevented consolidation and altered the
transient destabilization and re-stabilization of
β-catenin-cadherin interactions during memory formation.
Therefore, our findings suggest a general role for β-catenin
in the synaptic remodeling and stabilization underlying long-term
memory in adults.
Table of Contents
TABLE OF CONTENTS
CHAPTER 1...1
GENERAL INTRODUCTION...1
INTRODUCTION...2
Molecular mechanisms of synaptic
plasticity...2
Morphological changes associated with synaptic plasticity...3
Cell adhesion molecules and synaptic plasticity...4
β-CATENIN STRUCTURE AND FUNCTION...5
Structure of β-catenin...5
Functional roles of β-catenin...6
Posttranslational modifications regulate β-catenin
function...9
Role of β-catenin in presynaptic structure and
function...11
Role of β-catenin in postsynaptic structure and
function...15
Activity-dependent regulation of β-catenin...17
β-catenin and memory related pathology...19
β-catenin and Learning and Memory in the Adult Brain...21
CHAPTER 2...22
Β-CATENIN IS REQUIRED FOR MEMORY CONSOLIDATION...22
ABSTRACT...23
INTRODUCTION...23
RESULTS...25
β-catenin mRNA expression in the adult
mouse brain...25
β-catenin mRNA increases in the amygdala following fear
conditioning...27
β-catenin is post-translationally regulated following fear
conditioning...29
Increasing β-catenin functional stability results in an
enhancement in learning...35
Ctnnb1 deletion in the BLA does not alter baseline
measures...41
β-catenin is required for fear-memory
consolidation...47
β-catenin is not required for expression of fear
memory...51
DISCUSSION...54
METHODS...59
Animals...59
Immunoblotting...59
Immunoprecipitation...61
In situ hybridization...61
Lentiviral constructs and virus production...62
Surgery and injection of virus...62
Behavior...63
Elevated plus maze...63
Open field...63
Fear Conditioning Apparatus...63
Fear conditioning...64
Freezing apparatus...65
Data analysis...66
CHAPTER 3...67
WNT SIGNALING IN AMYGDALA-DEPENDENT LEARNING AND MEMORY...67
ABSTRACT...68
INTRODUCTION...68
RESULTS...71
Decreasing Wnt mediated signaling impairs memory
formation...71
Dkk-1 prevents learning-dependent re-stabilization between
β-catenin and cadherin...76
Genes in Wnt-mediated signaling are altered during memory
formation...78
Wnt1 gene expression changes with learning...82
Increasing Wnt1 impairs fear memory formation...86
Wnt1 prevents learning-dependent disassociation between β-catenin and cadherin...90
DISCUSSION...93
METHODS...97
Animals...97
Stereotaxic surgery and infusion of peptides...97
Immunoprecipitation and Immunoblotting...98
Immunohistochemistry...99
Behavioral studies...99
Open Field Behavior...99
Fear Conditioning Apparatus...100
Fear Conditioning...100
RNA extraction and cDNA synthesis...101
Real-time PCR...101
In situ hybridization...102
Data analysis...103
CHAPTER 4...104
Β-CATENIN IS REQUIRED FOR HIPPOCAMPAL-DEPENDENT LEARNING IN
ADULT MICE...104
ABSTRACT...105
INTRODUCTION...105
RESULTS...107
β-catenin deletion in the hippocampus does not alter
baseline activity or anxiety measures...107
β-catenin in the hippocampus is required
for context-dependent, but not cue-dependent fear memory
consolidation...111
β-Catenin deletion impairs object recognition
memory...113
β-Catenin deletion impairs consolidation, but not acquisition,
of spatial memory...115
DISCUSSION...117
METHODS...120
Animals...120
In situ hybridization...121
Lentiviral vectors and virus infection...121
Behavioral Studies...122
Open field...122
Elevated plus maze...122
Context-dependent fear conditioning...122
Cue-dependent fear conditioning...123
Novel object recognition...123
Morris Water Maze...125
Data analysis...126
CHAPTER 5...127
CONCLUDING REMARKS...127
SUMMARY OF FINDINGS...128
Dynamic Regulation of Cadherin/β-catenin
Interaction...135
Subcellular Distribution of β-Catenin...138
The Stabilization and De-Stabilization of Memory...139
Implications for Alzheimer's Disease...141
Role of β-catenin in development to disease...143
REFERENCES...144
TABLE OF FIGURES
FIGURE 2.3 - β-CATENIN EXPRESSION IN MICE...30
FIGURE 2.3- PHOSPHORYLATION STATE OF GSK-3β IS ALTERED AFTER
FEAR CONDITIONING...31
FIGURE 2.4 - PHOSPHORYLATION STATE OF β-CATENIN IS ALTERED
AFTER FEAR CONDITIONING...32
FIGURE 2.5 - COIMMUNOPRECIPITATION OF CADHERIN AND
β-CATENIN...34
FIGURE 2.6 - LICL DECREASES GSK-3β-MEDIATED β-CATENIN
PHOSPHORYLATION IN THE AMYGDALA...37
FIGURE 2.7 - LICL TREATMENT ENHANCES LEARNING...38
FIGURE 2.8 - LICL TREATMENT ENHANCES LEARNING...40
FIGURE 2.9 - REGION-SPECIFIC DELETION OF β-CATENIN IN THE
ADULT BRAIN...42
FIGURE 2.10 - CRESYL VIOLET (NISSL) STAINING OF INFECTED
BASOLATERAL AMYGDALA...44
FIGURE 2.11 - AMYGDALA-SPECIFIC β-CATENIN DELETIONS DO NOT
AFFECT BASELINE ANXIETY OR ACTIVITY MEASURES...46
FIGURE 2.12 - AMYGDALA-SPECIFIC CTNNB1 DELETION DOES NOT PREVENT
THE EXPRESSION, OF CONDITIONED FEAR...48
FIGURE 2.13 - AMYGDALA-SPECIFIC CTNNB1 DELETION PREVENTS THE
CONSOLIDATION OF CONDITIONED FEAR...50
FIGURE 2.14 - AMYGDALA-SPECIFIC CTNNB1 DELETION DOES NOT AFFECT THE
EXPRESSION OF CONDITIONED FEAR...53
FIGURE 3.1 - EXPRESSION OF DKK-1 IN THE AMYGDALA...72
FIGURE 3.2 - THE EFFECT OF DKK-1 IN THE AMYGDALA ON BASELINE
EMOTIONAL BEHAVIOR...73
FIGURE 3.3 - THE EFFECT OF DKK-1 IN THE AMYGDALA ON FEAR LEARNING
AND MEMORY...74
FIGURE 3.4 - THE EFFECT OF DKK-1 IN THE AMYGDALA ON FEAR LEARNING
AND MEMORY WHEN GIVEN PRIOR TO ACQUISITION...75
FIGURE 3.5 - THE EFFECT OF DKK-1 IN THE AMYGDALA ON FEAR LEARNING
AND MEMORY WHEN GIVEN IMMEDIATELY POST-ACQUISITION...76
FIGURE 3.6 - THE EFFECT OF FEAR CONDITIONING AND DKK-1
ADMINISTRATION ON THE INTERACTION BETWEEN β-CATENIN AND
CADHERIN...78
FIGURE 3.7 - TEMPORAL CHANGES IN WNT GENE EXPRESSION AFTER FEAR
CONDITIONING...81
FIGURE 3.8 - WNT1 MRNA EXPRESSION IN THE AMYGDALA...83
FIGURE 3.9 - WNT1 MRNA EXPRESSION IN THE AMYGDALA...85
FIGURE 3.10 - WNT1 EXPRESSION IN THE AMYGDALA...87
FIGURE 3.11 - THE EFFECT OF WNT1 IN THE AMYGDALA ON BASELINE
ANXIETY...88
FIGURE 3.12 - THE EFFECT OF WNT1 IN THE AMYGDALA ON FEAR LEARNING
AND MEMORY...89
FIGURE 3.13 - THE EFFECT OF WNT1 IN THE AMYGDALA ON FEAR LEARNING
AND MEMORY...90
FIGURE 3.14 - THE EFFECT OF FEAR CONDITIONING AND WNT1
ADMINISTRATION ON THE INTERACTION BETWEEN β-CATENIN AND
CADHERIN...92
FIGURE 4.1 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETIONS DO NOT
AFFECT BASELINE ACTIVITY OR ANXIETY MEASURES AS MEASURED BY OPEN
FIELD...109
FIGURE 4.2 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETIONS DO NOT
AFFECT BASELINE ACTIVITY AS MEASURED BY ELEVATED PLUS
MAZE...110
FIGURE 4.3 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETION PREVENTS
THE CONSOLIDATION, BUT NOT ACQUISITION OF CONTEXT-DEPENDENT FEAR
MEMORIES...112
FIGURE 4.4 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETION DOES NOT
AFFECT THE ACQUISITION OF CONSOLIDATION OF CUE-DEPENDENT FEAR
CONDITIONING...113
FIGURE 4.5 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETION IMPAIRS
OBJECT MEMORY...114
FIGURE 4.6 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETION DOES NOT
AFFECT THE ACQUISITION OF SPATIAL MEMORY...115
FIGURE 4.7 - HIPPOCAMPAL-SPECIFIC β-CATENIN DELETION DOES
IMPAIR CONSOLIDATED SPATIAL MEMORIES...117
FIGURE 5.1 - SCHEMATIC REPRESENTATION OF THE ROLE OF β-CATENIN
IN PRODUCING THE LABILE AND STABLE PHASES OF MEMORY
FORMATION...130
FIGURE 5.2 - SCHEMATIC REPRESENTATION OF THE EFFECT OF A WNT
ANTAGONIST AND WNT AGONIST ON THE LABILE AND STABLE PHASES OF
MEMORY FORMATION...133
FIGURE 5.3 - SCHEMATIC REPRESENTATION SHOWING A POSSIBLE
INTERACTION BETWEEN BDNF SIGNALING AND NMDAR ACTIVATION...137
TABLE OF TABLES
TABLE 1.1 EFFECTS OF LOSS OF FUNCTION OR OVEREXPRESSION OF
β-CATENIN ON PRESYNAPTIC AND POSTSYNAPTIC FUNCTION...12
TABLE 3.1 - TEMPORAL CHANGES, EXPRESSED AS FOLD REGULATION, IN THE
EXPRESSION OF 84 GENES RELATED TO WNT-MEDIATED SIGNALING FOLLOWING
FEAR CONDITIONING...80
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