The Role of Stress in Two Genetic Models of Epilepsy Public
Sawyer, Nikki T. (2014)
Abstract
Human studies show a link between stress and epilepsy, with stress causing an increase in seizure frequency and severity in patients with epilepsy. While many different animal model systems have been used to better understand this connection and the possible mechanisms involved, results have not been clear. Furthermore, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. To address this question, we examined the relationship between stress and seizure outcome in two genetic models of epilepsy that carry mutations in voltage-gated sodium channels (VGSCs) Scn8a and Scn1a. Scn8amed/+ mutants display spontaneous absence seizures and an increased threshold to induced seizures. Scn1aRH/+ mutants exhibit spontaneous convulsive seizures and a reduced threshold to induced seizures. In the experiments described herein we demonstrate that the VGSC mutations can affect the stress response, seizure outcomes following either a stressor or altered early life experience, and behavior. Scn8amed/+ mutants respond to stress differently from their wildtype (WT) littermates, and higher levels of anxiety-like behaviors may be driving the seizure response to a stressor in this model. Stress also negatively affects the Scn1aRH/+ mutants, but in a similar manner to their WT littermates. The Scn8amed/+ line and Scn1aRH/+ line are maintained on different mouse strains, suggesting that genetic background and the presence of modifier genes may also affect the seizure response to a stressor. We also demonstrate that experiences encountered early in life can modify seizure outcome in adult animals in ways that depend on both the genetic makeup of the organism and sex of the organism. Overall, we show that altered neural excitability due to an epilepsy-causing mutation can affect the stress response, seizure outcomes following either a stressor or altered early life experience, and behavior. These results highlight the importance of using genetic models of epilepsy to better understand how stress is working to influence seizure activity.
Table of Contents
CHAPTER 1: STRESS AND EPILEPSY: MULTIPLE MODELS, MULTIPLE OUTCOMES 1
1.1 Abstract 2
1.2 Introduction 3
1.3 Human Studies 5
1.4 Animal Studies 7
1.4.1 Seizure Susceptibility and the HPA axis 7
1.4.2 Effects of CRH on Seizures 9
1.4.3 Effects of ACTH on Seizures 9
1.4.4 Effects of CORT on Seizures 10
1.4.5 Acute Stress and Seizures 13
1.4.6 Chronic Stress and Seizures 16
1.4.7 Early Life Stress and Seizures 17
1.5 Possible Mechanisms 19
1.6 Multiple Models; Multiple Outcomes 21
1.7 Genetic Mouse Models of Epilepsy 22
1.8 Conclusion 25
1.9 Acknowledgements 26
CHAPTER 2: SCN8A VOLTAGE-GATED SODIUM CHANNEL MUTATION ALTERS SEIZURE AND ANXIETY RESPONSES TO ACUTE STRESS 27
2.1 Abstract 28
2.2 Introduction 29
2.3 Methods and Materials 32
2.4 Results 39
2.4.1 Scn8amed/+ mice have frequent spontaneous SWDs 39
2.4.2 Acute stress increases SWD frequency in Scn8amed/+ mice 39
2.4.3 Acute stress affects SWD rhythm in Scn8amed/+ mice for up to 60 hours after the stress exposure 42
2.4.4 Acute stress reduces latencies to and increases severity of picrotoxin-induced and kainic acid-induced seizures in Scn8amed/+ mice 44
2.4.5 Scn8amed/+ Mice have normal HPA axis activity 48
2.4.6 Acute stress affects HPA axis circadian activity in Scn8amed/+ mice for up to 12 hours after the stress exposure 48
2.4.7 Scn8amed/+ mice show increased anxiety-like behavior 50
2.5 Discussion 52
2.6 Acknowledgements 59
CHAPTER 3: EARLY LIFE EXPERIENCE ALTERS ADULT SEIZURE OUTCOME AND BEHAVIOR IN A VOLTAGE-GATED SODIUM CHANNEL (SCN8A) MUTANT 60
3.1 Abstract 61
3.2 Introduction 62
3.3 Methods and Materials 64
3.4 Results 71
3.4.1 Maternal separation (MS) paradigm unexpectedly increases maternal behavior in C3HeB/FeJ dams 71
3.4.2 MS affects weight gain in both males and females, with stronger effects in males; Genotype affects weight in adult females 71
3.4.3 Baseline SWD activity and circadian rhythm of SWDs remain unchanged 74
3.4.4 MS affects SWD response to acute stress in male Scn8amed/+ mutants only 74
3.4.5 DH Females have a larger SWD response to acute stress than DH males 76
3.4.6 Long-term effect of restraint stress on SWD activity remains unchanged 77
3.4.7 MS improves flurothyl-induced seizure outcome in Scn8amed/+ females only 77
3.4.8 MS improves picrotoxin-induced seizure outcome in Scn8amed/+ males only 78
3.4.9 DH females are more resistant to picrotoxin-induced seizures than DH males 80
3.4.10 MS reduces the CORT response to an acute stressor in females only 82
3.4.11 MS affects males and females differently in open field measures 83
3.4.12 MS mildly affects novel cage and forced swim behavior in females 86
3.5 Discussion 89
3.5.1 Effects of MS 90
3.5.2 Effects of Genotype 91
3.5.3 Effects of Sex 92
3.5.4 MS-Sex Interactions 93
3.5.5 MS-Genotype Interactions 95
3.5.6 Sex-Genotype Interactions 97
3.6 Conclusion 98
3.7 Acknowledgements 99
CHAPTER 4: DYSFUNCTION OF THE VOLTAGE-GATED SODIUM CHANNEL GENE SCN1A ALTERS BEHAVIOR, BUT NOT THE SEIZURE RESPONSE TO STRESS 100
4.1 Abstract 101
4.2 Introduction 102
4.3 Methods 104
4.4 Results 115
4.4.1 N12 Scn1aRH mutants exhibit a shortened life span, spontaneous seizures, and a reduced latency to flurothyl-induced seizures 115
4.4.2 Scn1aRH/+ mutants are hyperactive 118
4.4.3 Scn1aRH/+ mutants show mild cognitive impairment and deficits in sensorimotor gating 120
4.4.4 Scn1aRH/+ mutants show a deficit in risk assessment ability 123
4.4.5 Scn1aRH/+ mutants show mild social deficits 127
4.4.6 Stress worsens seizure outcome in Scn1aRH/+ mutants 130
4.4.7 Scn1aRH/+ mutants have similar HPA axis function as WT littermates 133
4.4.8 Scn1aRH/+ mutants do not show any depressive-like behaviors 133
4.5 Discussion 134
4.6 Acknowledgements 141
CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS 142
5.1 Summary 143
5.2 VGSCs and the Response to Acute Stress 144
5.2.1 Short-Term Effects of Acute Stress on Spontaneous Seizures 145
5.2.2 Short-Term Effects of Acute Stress on Induced Seizures 148
5.2.3 Long-Term Effects of Acute Stress 151
5.3 VGSCs and Early Life Experience 153
5.4 VGSCs and Behavior 157
5.4.1 Anxiety- and Depressive-Like Behaviors 158
5.4.2 Social Behavior 159
5.4.3 Other Behavior Findings 160
5.5 Future Directions 162
5.5.1 Further Characterization of the HPA Axis of VGSC Mutants 162
5.5.2 Role of Anxiety in the Stress Response of VGSC Mutants 164
5.5.3 Effect of Stress on Sleep Patterns in VGSC Mutants 165
5.5.4 Role of Sex Hormones in VGSC Expression and Function 166
5.6 Overall Conclusions 167
REFERENCES 169
APPENDIX A: FULL DATA SET FROM SCN8AMED MS EXPERIMENTS 207
A1 Baseline Spontaneous SWD Activity from MS Experiments 208
A2 Post-Stress Response in MS Experiments 209
A3 Flurothyl Results from MS Experiments 211
A4 Picrotoxin Results from MS Experiments 212
A5 Sex Differences in CORT Levels 213
APPENDIX B: ADDITONAL DATA FROM SCN1ARH/+ EXPERIMENTS 214
B1 Hyperactivity in other Behavioral Tasks in Scn1a R1648H 215
B2 Additional Risk Assessment Tasks - Scn1a R1648H 216
B2.1 Methods 216
B2.2 Results 217
B3 Depressive-Like Behavioral Tasks - Scn1a R1648H 219
B3.1 Methods 219
B3.2 Results 219
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