Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Chen, Lingxuan; Saito, Takashi; Saido, Takaomi C.; Módy, István

doi:10.1523/eneuro.0059-18.2018

Cited by 24 publications

(28 citation statements)

References 67 publications

(103 reference statements)

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“…Our findings indicate an age-dependent increase in Aβ1–42 levels and plaque deposition that are consistent with previous research 19,21,32 . Previous reports indicated the absence of hyperexcitability in the App NL-G-F at 8 and 12 months of age 24 and subtle synaptic alterations at around 18 months 50 . However, other reports have indicated theta-gamma coupling impairments in the entorhinal cortex of App NL-G-F mice at 5 months of age 51 and hypersynchronous functional connectivity of brain networks using resting-state functional MRI in App NL-G-F mice at 3 months (pre-plaque stage) 52 .…”

Section: Discussionmentioning

confidence: 85%

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

Jacob

Davies

Bock

et al. 2019

Sci Rep

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Multiple animal models have been created to gain insight into Alzheimer’s disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid β plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aβ1–42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

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Section: Discussionmentioning

confidence: 85%

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

Jacob

Davies

Bock

et al. 2019

Sci Rep

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“…In addition, SST interneurons such as oriens lacunosum-moleculare (O-LM) cells show enhanced responses to theta frequency inputs (Pike et al 2000;Zemankovics et al 2010;Whittington and Traub 2003), while PV interneurons such as basket cells show enhanced responses to gamma frequency inputs (Pike et al 2000;Zemankovics et al 2010), further indicating their cell type-specific involvement in theta and gamma oscillations. Recent experimental evidence revealed that SST and PV interneurons disintegrate structurally and functionally in mouse models of AD (Palop et al 2007;Schmid et al 2016;Chen et al 2018;Verret et al 2012;Martinez-Losa et al 2018;Iaccarino et al 2016), suggesting that dysfunctions of SST and PV interneurons may underlie impairments of theta and gamma oscillations observed in AD. Optogenetic activation (Iaccarino et al 2016) or molecular manipulation (Martinez-Losa et al 2018;Zhang et al 2017) of PV interneurons could restore impaired hippocampal gamma oscillations in mouse models of AD.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid β oligomers in vivo

et al. 2020

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Accumulation of amyloid β oligomers (AβO) in Alzheimer's disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether AβO causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in AβO-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in AβO-injected mice selectively restored AβOinduced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from AβO-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus-response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that AβO increased the initial GABA release probability to depress SST/PV interneuron's inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons' input to CA1 PC as the synaptic mechanisms underlying AβO-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.

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“…Fewer studies exist of second-generation APP knock-in models which address the APP overexpression problem, yet have less pronounced disease phenotypes (Sasaguri et al, 2017). In one relevant study, sIPSC amplitude from putative PV cells is decreased in parietal cortex PCs from 18-to 20-month App NL-F mice, although synaptic E/I balance is unchanged (Chen et al, 2018). It will be critical to study hippocampal network alterations, both at the level of the microcircuit and behaving animal, in novel AD mouse models with greater validity.…”

Section: Swr Alterations In Aging and Diseasementioning

confidence: 99%

Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer's Disease

et al. 2020

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Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the microcircuitry underlying these disruptions is underexplored. We tested whether a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female three-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs (sPCs) having a higher probability of spiking during SWRs. Both deep PCs (dPCs) and sPCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC microcircuit also contribute to impairment.

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Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Cited by 24 publications

References 67 publications

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid β oligomers in vivo

Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer's Disease

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