bioRxiv (Cold Spring Harbor Laboratory), May 16, 2020
We thank Drs Julija Krupic and Mohamady El Gaby for introducing us to recordings in freely moving... more We thank Drs Julija Krupic and Mohamady El Gaby for introducing us to recordings in freely moving animals.
The hippocampus plays a central role in long-term memory formation, and different hippocampal net... more The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neurons to understand how cholinergic activity affects different stages of spatial memory formation in a reward-based navigation task in mice. We found that optogenetic stimulation of septal cholinergic neurons (1) impaired memory formation when activated at goal location but not during navigation; (2) reduced sharp wave-ripple (SWR) incidence at goal location; and (3) reduced SWR incidence and enhanced the-ta-gamma oscillations during sleep. These results underscore the importance of appropriate timing of cholinergic input in long-term memory formation, which might help explain the limited success of cholinesterase inhibitor drugs in treating ...
Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. A... more Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt−/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ1–42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt−/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt−/− mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25–6981. To further investigate a possible difference in GluN2B-containing ...
Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer's disease. A... more Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer's disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt −/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ 1-42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt −/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt −/− mice, while the NMDAR current was reduced to a similar extent by the GluN2Bselective NMDAR antagonist Ro 25-6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt −/− mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt −/− mice, thus differential NMDAR subunit expression does not explain the difference in hAβ effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hAβ in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hAβ exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to Aβ and that a genetic knock out of tau protein protects them from Aβ synaptotoxicity.
bioRxiv (Cold Spring Harbor Laboratory), May 16, 2020
We thank Drs Julija Krupic and Mohamady El Gaby for introducing us to recordings in freely moving... more We thank Drs Julija Krupic and Mohamady El Gaby for introducing us to recordings in freely moving animals.
The hippocampus plays a central role in long-term memory formation, and different hippocampal net... more The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neurons to understand how cholinergic activity affects different stages of spatial memory formation in a reward-based navigation task in mice. We found that optogenetic stimulation of septal cholinergic neurons (1) impaired memory formation when activated at goal location but not during navigation; (2) reduced sharp wave-ripple (SWR) incidence at goal location; and (3) reduced SWR incidence and enhanced the-ta-gamma oscillations during sleep. These results underscore the importance of appropriate timing of cholinergic input in long-term memory formation, which might help explain the limited success of cholinesterase inhibitor drugs in treating ...
Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. A... more Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt−/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ1–42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt−/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt−/− mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25–6981. To further investigate a possible difference in GluN2B-containing ...
Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer's disease. A... more Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer's disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt −/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ 1-42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt −/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt −/− mice, while the NMDAR current was reduced to a similar extent by the GluN2Bselective NMDAR antagonist Ro 25-6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt −/− mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt −/− mice, thus differential NMDAR subunit expression does not explain the difference in hAβ effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hAβ in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hAβ exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to Aβ and that a genetic knock out of tau protein protects them from Aβ synaptotoxicity.
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