Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta
<p>Amyloid beta (ABeta) and tau protein are both implicated in memory impairment in early Alzheimer’s disease, but whether and how they interact to cause synaptic dysfunction are unknown. Consequently, I firstly investigated whether tau protein is required for the robust phenomenon of ABeta-in...
| Main Authors: | , |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2014
|
| Subjects: |
| _version_ | 1826286316223987712 |
|---|---|
| author | Shipton, O Olivia Shipton |
| author2 | Bannerman, D |
| author_facet | Bannerman, D Shipton, O Olivia Shipton |
| author_sort | Shipton, O |
| collection | OXFORD |
| description | <p>Amyloid beta (ABeta) and tau protein are both implicated in memory impairment in early Alzheimer’s disease, but whether and how they interact to cause synaptic dysfunction are unknown. Consequently, I firstly investigated whether tau protein is required for the robust phenomenon of ABeta-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. I demonstrate that the absence of tau prevents the ABeta-induced impairment of LTP; moreover, a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks both an ABeta-induced increase in tau phosphorylation and the ABeta-induced LTP impairment. Thus, tau protein, likely in its phosphorylated form, is required for ABeta to impair LTP. Secondly, I investigated the underlying mechanisms for this ABeta-induced impairment and find that ABeta changes the balance between the two major types of glutamate receptors involved in plasticity processes, with a specific effect on GluN2B subunit-containing NMDA receptors. Since the distribution of these receptors is asymmetric between the left and right mouse hippocampus, I accessed these different types of synapses optogenetically and found that only the GluN2B-rich synapses receiving left CA3 input show ABeta-induced changes in the balance of glutamate receptors, suggesting an asymmetry in synaptic vulnerability to ABeta. Moreover, there was a left-right difference in tetanus-induced LTP and therefore, thirdly, I investigated whether mice have a hemispheric dissociation in memory processing using acute optogenetic silencing of left or right CA3 during hippocampus-dependent memory tasks. Unilateral silencing of either the left or the right CA3 caused a deficit in short-term memory, but only left CA3 silencing impaired performance on a spatial long-term memory task. Together, these results suggest that memory may be routed via distinct left-right pathways within the mouse hippocampus, and that neural pathways subserving distinct functions may also be differentially vulnerable to pathological changes at the synaptic level.</p> |
| first_indexed | 2024-03-07T01:41:57Z |
| format | Thesis |
| id | oxford-uuid:972d7dbf-fcf1-4f84-9a84-406418dbc7fb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:41:57Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:972d7dbf-fcf1-4f84-9a84-406418dbc7fb2022-03-26T23:57:39ZAsymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid betaThesishttp://purl.org/coar/resource_type/c_db06uuid:972d7dbf-fcf1-4f84-9a84-406418dbc7fbPhysiology and anatomyLife SciencesNeuroscienceMemoryBiology (medical sciences)LearningBehavioural NeurosciencePhysiologyMedical SciencesBiologyEnglish2014Shipton, OOlivia ShiptonBannerman, DPaulsen, O<p>Amyloid beta (ABeta) and tau protein are both implicated in memory impairment in early Alzheimer’s disease, but whether and how they interact to cause synaptic dysfunction are unknown. Consequently, I firstly investigated whether tau protein is required for the robust phenomenon of ABeta-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. I demonstrate that the absence of tau prevents the ABeta-induced impairment of LTP; moreover, a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks both an ABeta-induced increase in tau phosphorylation and the ABeta-induced LTP impairment. Thus, tau protein, likely in its phosphorylated form, is required for ABeta to impair LTP. Secondly, I investigated the underlying mechanisms for this ABeta-induced impairment and find that ABeta changes the balance between the two major types of glutamate receptors involved in plasticity processes, with a specific effect on GluN2B subunit-containing NMDA receptors. Since the distribution of these receptors is asymmetric between the left and right mouse hippocampus, I accessed these different types of synapses optogenetically and found that only the GluN2B-rich synapses receiving left CA3 input show ABeta-induced changes in the balance of glutamate receptors, suggesting an asymmetry in synaptic vulnerability to ABeta. Moreover, there was a left-right difference in tetanus-induced LTP and therefore, thirdly, I investigated whether mice have a hemispheric dissociation in memory processing using acute optogenetic silencing of left or right CA3 during hippocampus-dependent memory tasks. Unilateral silencing of either the left or the right CA3 caused a deficit in short-term memory, but only left CA3 silencing impaired performance on a spatial long-term memory task. Together, these results suggest that memory may be routed via distinct left-right pathways within the mouse hippocampus, and that neural pathways subserving distinct functions may also be differentially vulnerable to pathological changes at the synaptic level.</p> |
| spellingShingle | Physiology and anatomy Life Sciences Neuroscience Memory Biology (medical sciences) Learning Behavioural Neuroscience Physiology Medical Sciences Biology Shipton, O Olivia Shipton Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title | Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title_full | Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title_fullStr | Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title_full_unstemmed | Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title_short | Asymmetry of hippocampal function in mice: left-right differences in memory processing and vulnerability to amyloid beta |
| title_sort | asymmetry of hippocampal function in mice left right differences in memory processing and vulnerability to amyloid beta |
| topic | Physiology and anatomy Life Sciences Neuroscience Memory Biology (medical sciences) Learning Behavioural Neuroscience Physiology Medical Sciences Biology |
| work_keys_str_mv | AT shiptono asymmetryofhippocampalfunctioninmiceleftrightdifferencesinmemoryprocessingandvulnerabilitytoamyloidbeta AT oliviashipton asymmetryofhippocampalfunctioninmiceleftrightdifferencesinmemoryprocessingandvulnerabilitytoamyloidbeta |