Abstract
BackgroundAbnormal accumulation of amyloid β1–42 oligomers (AβO1–42), a hallmark of Alzheimer’s disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AβO1–42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AβO1–42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP.ResultsTargeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AβO1–42 causes synapse-specific dysfunction in PV and SST interneurons. AβO1–42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AβO1–42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AβO1–42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction.ConclusionsOur results reveal that AβO1–42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer’s disease.
Highlights
Abnormal accumulation of amyloid β1–42 oligomers (AβO1–42), a hallmark of Alzheimer’s disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory
To induce blue light-induced theta-nested gamma oscillations, we injected adeno-associated virus (AAV) carrying ChR2 (AAV-CaMKII-ChR2-mCherry) into the CA1 area of the hippocampus (Fig. 1b), which led to the expression of ChR2 in CA1 pyramidal cells (PC) in hippocampal slices in vitro (Fig. 1c)
Phase-amplitude coupling analysis of gamma oscillations to the trough of theta cycle (Fig. 1k) revealed that the coupling strength, quantified by the modulation index, was significantly decreased by AβO1–42, but not by AβO42–1, compared to that in the dimethyl sulfoxide (DMSO)-treated slices (Fig. 1l). We replicated these effects in different slices treated with AβO1–42 for 20 min before performing field recording (Additional file 3: Figure S3); the reduction in oscillatory activity was not caused by recording duration. These results show that AβO1–42-treated slices with optical stimulation of ChR2-expressing CA1 PCs can replicate gamma oscillations impairment as observed in Alzheimer’s disease mouse models in vivo [5,6,7,8]
Summary
Abnormal accumulation of amyloid β1–42 oligomers (AβO1–42), a hallmark of Alzheimer’s disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Optogenetic stimulation of channelrhodopsin-2 (ChR2)-expressing hippocampal CA1 pyramidal cells (PCs) at theta-frequency was shown to induce in vivo-like theta-nested gamma oscillations in the CA1 area of acute hippocampal slices in vitro [34] This provides a novel model in which to perform targeted whole-cell patch-clamp recordings and selective optogenetic modulation of PV or SST interneuron activity during optogenetically induced theta-nested gamma oscillations and LTP induction. We have used this approach to investigate neural circuit dysfunction in hippocampal slices treated with AβO1–42. Using a computational network model of PC, PV, and SST interneurons, we further demonstrate that PV and SST interneurons targeting different compartments of the CA1 PC have distinct functional roles in oscillogenesis and tLTP induction
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