Title Page
Contents
ABSTRACT 11
Chapter 1. Introduction 14
1.1. FKBP5 (FK506 binding protein 51) 14
1.1.1. Role of FKBP5 in GR signaling and stress response 14
1.1.2. Behavioral impact of FKBP5 modulation 15
1.1.3. Involvement of FKBP5 in other molecular processes 15
1.2. Brain areas mediating the stress response 16
1.2.1. The paraventricular nucleus of the hypothalamus 16
1.2.2. The hippocampus 17
1.2.3. Other brain regions in stress responses 17
1.3. Synaptic plasticity and the impact of stress 18
1.3.1. The paraventricular nucleus of the hypothalamus 18
1.3.2. The hippocampus 19
1.4. Purpose of study 20
Chapter 2. Altered short-term synaptic plasticity in the paraventricular nucleus of the hypothalamus in FKBP5-deficient mice 22
2.1. Introduction 22
2.2. Materials and Methods 24
2.2.1. Animals 24
2.2.2. Slice preparation 24
2.2.3. Electrophysiological experiments 24
2.2.4. Data Analysis 26
2.3. Results 27
2.3.1. Selectively response to stress in neuronal excitability and transmission in FKBP5-deficient PVN neurons 27
2.3.2. Enhanced NMDAR-mediated synaptic transmission in FKBP5-deficient PVN neurons 28
2.3.3. No change in synaptic plasticity of stress-exposed FKBP5-deficient PVN neurons 29
2.3.4. Inactivation of TrkB receptors initiates stress responses from the FKBP5-deficient neurons 30
2.3.5. Inhibition of PLC has little effect on the stress response in FKBP5-deficient neurons 31
2.3.6. Inhibition of PI3-K elicits stress responses from the FKBP5-deficient neurons 33
2.4. Discussion 44
Chapter 3. Altered inhibitory long-term synaptic depression in the paraventricular nucleus of the hypothalamus in FKBP5-deficient mice 46
3.1. Introduction 46
3.2. Materials and Methods 48
3.2.1. Animals 48
3.2.2. Slice preparation 48
3.2.3. Electrophysiological experiments 48
3.2.4. Data Analysis 49
3.3. Results 50
3.3.1. FKBP5 deficiency unmasked inhibitory synaptic plasticity of the PVN 50
3.3.2. Unmasked inhibitory synaptic plasticity mediated GR activation in FKBP5-deficient mice 51
3.3.3. Retrograde signals mediated inhibitory synaptic plasticity in FKBP5-deficient mice 52
3.3.4. Blockade of TrkB receptors inhibits inhibitory synaptic plasticity in FKBP5-deficient mice 54
3.4. Discussion 61
Chapter 4. Interaction between glucocorticoid receptors and FKBP5 in regulating neurotransmission of the hippocampus 63
4.1. Introduction 63
4.2. Materials and Methods 65
4.2.1. Animals 65
4.2.2. Slice preparation 65
4.2.3. Electrophysiological experiments 65
4.2.4. Data Analysis 66
4.3. Results 68
4.3.1. FKBP5 deficiency slightly altered the spontaneous synaptic transmission of the hippocampus 68
4.3.2. FKBP5 deficiency altered the action outcome of GRs in the hippocampus 69
4.3.3. FKBP5 deficiency altered evoked synaptic transmission and effect of GR activation of the hippocampus 71
4.4. Discussion 76
Chapter 5. Selectively impairment of long-term depression in FKBP5-deficient hippocampus 80
5.1. Introduction 80
5.2. Materials and Methods 82
5.2.1. Animals 82
5.2.2. Slice preparation 82
5.2.3. Electrophysiological experiments 82
5.2.4. Lysate preparation and Western blot analysis 83
5.2.5. Data Analysis 84
5.3. Results 85
5.3.1. FKBP5 deficiency altered synaptic responsiveness and neuronal excitability of the hippocampus 85
5.3.2. FKBP5 deficiency blunted GR actions of the hippocampus 85
5.3.3. FKBP5 deficiency altered bidirectional synaptic plasticity of the hippocampus 86
5.3.4. FKBP5 deficiency insensitive to the action of GRs in the bidirectional synaptic plasticity of the hippocampus 86
5.3.5. FKBP5 deficiency altered depotentiation of the hippocampus 87
5.3.6. FKBP5 deficiency independence on mGluR1 or CB1R-mediated LTD of the hippocampus 88
5.3.7. FKBP5 deficiency selective impaired LTD caused by increased expression of calcineurin 89
5.3.8. FKBP5 deficiency altered on bidirectional synaptic plasticity in female 90
5.3.9. FKBP5 deficiency selective impaired LTD caused by BDNF-TrkB signaling 91
5.3.10. FKBP5 deficiency selective impaired LTD caused by activation of PLC downstream of BDNF-TrkB signaling 92
5.3.11. Impaired hippocampal LTD in female FKBP5 KO mice caused by the action of BDNF-TrkB signaling and ERs 92
5.4. Discussion 103
Chapter 6. Conclusions 106
References 111
Appendices 139
[Appendix 1] List of Abbreviations 139
[Appendix 2] List of publications 141
Abstract (in Korean) 142
Figure 2.1. Selectively neuronal properties responding to stress in the PVN of FKBP5 KO mice 35
Figure 2.2. Stress-induced NMDAR-mediated sEPSC is decreased in the PVN of WT mice but not in the PVN of FKBP5 KO mice 36
Figure 2.3. Stress-induced STP is induced in the PVN of WT mice but not in the PVN of FKBP5 KO mice 37
Figure 2.4. Systemic injection of TrkB antagonist rescued impaired stress-induced synaptic plasticity in the PVN of FKBP5 KO mice 39
Figure 2.5. Systemic injection of PLC inhibitor is minimal change in stress-induced synaptic plasticity in the PVN of FKBP5 KO mice 41
Figure 2.6. Selective inhibition of PI3-K rescued impaired stress-induced synaptic plasticity in plasticity in the PVN of FKBP5 KO mice 43
Figure 3.1. iLTD is unmasked in the PVN of FKBP5 KO mice 56
Figure 3.2. Inhibition of GR is blocked iLTD in the PVN of WT and FKBP5 KO mice 57
Figure 3.3. Activation of mGluR5 is required for induction of iLTD in FKBP5 KO mice 58
Figure 3.4. Activation of the opioid receptor is required for induction of iLTD in FKBP5 KO mice 59
Figure 3.5. Unmasked iLTD in FKBP5 KO mice is caused by BDNF-TrkB signaling 60
Figure 4.1. Basal synaptic transmission onto hippocampal neurons of WT and FKBP5 KO mice 73
Figure 4.2. Spontaneous network synaptic activity onto hippocampal neurons of WT and FKBP5 KO mice 74
Figure 4.3. Evoked synaptic transmission onto hippocampal neurons of WT and FKBP5 KO mice 75
Figure 5.1. fEPSP I-O curve and neuronal excitability onto hippocampal neurons of WT and FKBP5 KO mice 94
Figure 5.2. fEPSP 1xTBS-induced LTP in the hippocampus of WT and FKBP5 KO mice 95
Figure 5.3. LFS-induced LTD in the hippocampus of WT and FKBP5 KO mice 96
Figure 5.4. Depotentiation in the hippocampus of WT and FKBP5 KO mice 97
Figure 5.5. mGluR1-and CB1R-LTD in the hippocampus of WT and FKBP5 KO mice 98
Figure 5.6. Pharmacological modulation of calcineurin recovered LFS-induced LTD in the hippocampus of FKBP5 KO mice 99
Figure 5.7. Hippocampal bidirectional synaptic plasticity in female WT and FKBP5 KO mice 100
Figure 5.8. Blockade of the TrkB receptor prevents LTD impairment in the hippocampus of FKBP5 KO mice 101
Figure 5.9. Blockade of PLC is the opposite effect on hippocampal LTD in male WT and FKBP5 KO mice 101
Figure 5.10. Blockade of both BDNF-TrkB signaling and ER is recovered impaired hippocampal LTD in female FKBP5 KO mice 102
Figure 6.1. The impact of FKBP5 deficiency on the central nervous system 110