Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus
Abstract Mutations in the Presenilin genes (PSEN1 and PSEN2) are the major cause of familial Alzheimer’s disease (AD), highlighting the importance of Presenilin (PS) in AD pathogenesis. Previous studies of PS function in the hippocampus demonstrated that loss of PS results in the impairment of short...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Molecular Brain |
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| Online Access: | https://doi.org/10.1186/s13041-023-01009-x |
| _version_ | 1811171490039595008 |
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| author | Sang Hun Lee Vadim Y. Bolshakov Jie Shen |
| author_facet | Sang Hun Lee Vadim Y. Bolshakov Jie Shen |
| author_sort | Sang Hun Lee |
| collection | DOAJ |
| description | Abstract Mutations in the Presenilin genes (PSEN1 and PSEN2) are the major cause of familial Alzheimer’s disease (AD), highlighting the importance of Presenilin (PS) in AD pathogenesis. Previous studies of PS function in the hippocampus demonstrated that loss of PS results in the impairment of short- and long-term synaptic plasticity and neurotransmitter release at hippocampal Schaffer collateral (SC) and mossy fiber (MF) synapses. Cortical input to the hippocampus through the lateral perforant pathway (LPP) and the medial perforant pathway (MPP) is critical for normal cognitive functions and is particularly vulnerable during aging and early stages of AD. Whether PS regulates synaptic function in the perforant pathways, however, remained unknown. In the current study, we investigate PS function in the LPP and MPP by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from postnatal forebrain-restricted excitatory neuron-specific PS conditional double knockout (cDKO) mice. We found that paired-pulse ratio (PPR) is reduced in the LPP and MPP of PS cDKO mice. Moreover, synaptic frequency facilitation or depression in the LPP or MPP, respectively, is impaired in PS cDKO mice. Notably, depletion of intracellular Ca2+ stores by inhibition of sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) minics and occludes the effects of PS inactivation, as evidenced by decreases of the evoked excitatory postsynaptic currents (EPSCs) amplitude in the LPP and MPP of control neurons but no effect on the EPSC amplitude in PS cDKO neurons, suggesting that impaired intracellular calcium homeostasis in the absence of PS may contribute to the observed deficits in synaptic transmission. While spontaneous synaptic events, such as both the frequency and the amplitude of spontaneous or miniature EPSCs, are similar between PS cDKO and control neurons, long-term potentiation (LTP) is impaired in the LPP and MPP of PS cDKO mice, accompanied with reduction of evoked NMDA receptor-mediated responses. These findings show the importance of PS in the regulation of synaptic plasticity and intracellular calcium homeostasis in the hippocampal perforant pathways. |
| first_indexed | 2024-04-10T17:14:48Z |
| format | Article |
| id | doaj.art-1ed3f9ae389046659f943b531870fe49 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-04-10T17:14:48Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-1ed3f9ae389046659f943b531870fe492023-02-05T12:27:23ZengBMCMolecular Brain1756-66062023-01-0116111210.1186/s13041-023-01009-xPresenilins regulate synaptic plasticity in the perforant pathways of the hippocampusSang Hun Lee0Vadim Y. Bolshakov1Jie Shen2Department of Neurology, Brigham & Women’s Hospital, Harvard Medical SchoolDepartment of Psychiatry, McLean Hospital, Harvard Medical SchoolDepartment of Neurology, Brigham & Women’s Hospital, Harvard Medical SchoolAbstract Mutations in the Presenilin genes (PSEN1 and PSEN2) are the major cause of familial Alzheimer’s disease (AD), highlighting the importance of Presenilin (PS) in AD pathogenesis. Previous studies of PS function in the hippocampus demonstrated that loss of PS results in the impairment of short- and long-term synaptic plasticity and neurotransmitter release at hippocampal Schaffer collateral (SC) and mossy fiber (MF) synapses. Cortical input to the hippocampus through the lateral perforant pathway (LPP) and the medial perforant pathway (MPP) is critical for normal cognitive functions and is particularly vulnerable during aging and early stages of AD. Whether PS regulates synaptic function in the perforant pathways, however, remained unknown. In the current study, we investigate PS function in the LPP and MPP by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from postnatal forebrain-restricted excitatory neuron-specific PS conditional double knockout (cDKO) mice. We found that paired-pulse ratio (PPR) is reduced in the LPP and MPP of PS cDKO mice. Moreover, synaptic frequency facilitation or depression in the LPP or MPP, respectively, is impaired in PS cDKO mice. Notably, depletion of intracellular Ca2+ stores by inhibition of sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) minics and occludes the effects of PS inactivation, as evidenced by decreases of the evoked excitatory postsynaptic currents (EPSCs) amplitude in the LPP and MPP of control neurons but no effect on the EPSC amplitude in PS cDKO neurons, suggesting that impaired intracellular calcium homeostasis in the absence of PS may contribute to the observed deficits in synaptic transmission. While spontaneous synaptic events, such as both the frequency and the amplitude of spontaneous or miniature EPSCs, are similar between PS cDKO and control neurons, long-term potentiation (LTP) is impaired in the LPP and MPP of PS cDKO mice, accompanied with reduction of evoked NMDA receptor-mediated responses. These findings show the importance of PS in the regulation of synaptic plasticity and intracellular calcium homeostasis in the hippocampal perforant pathways.https://doi.org/10.1186/s13041-023-01009-xAlzheimer’s diseaseConditional knockoutHippocampusPerforant pathwaysShort-term synaptic plasticityLong-term potentiation |
| spellingShingle | Sang Hun Lee Vadim Y. Bolshakov Jie Shen Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus Molecular Brain Alzheimer’s disease Conditional knockout Hippocampus Perforant pathways Short-term synaptic plasticity Long-term potentiation |
| title | Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| title_full | Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| title_fullStr | Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| title_full_unstemmed | Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| title_short | Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| title_sort | presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus |
| topic | Alzheimer’s disease Conditional knockout Hippocampus Perforant pathways Short-term synaptic plasticity Long-term potentiation |
| url | https://doi.org/10.1186/s13041-023-01009-x |
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