Alzheimer’s pathology causes impaired inhibitory connections and reactivation of spatial codes during spatial navigation

Prince, Stephanie M.; Paulson, Abigail L.; Jeong, Nuri; Zhang, Lu; Amigues, Solange; Singer, Annabelle C.

doi:10.1016/j.celrep.2021.109008

Cited by 38 publications

(29 citation statements)

References 114 publications

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“…The CA1 deficits instead could reflect weaker population drive or coordination of CA1, through post-synaptic deficits, or CA1 circuit cell-specific excitability impairments. A prior study investigating synaptic function in behaving 5xFAD mice found impaired inhibitory interneuronal connections onto CA1 pyramidal cells and disrupted sharp-wave ripples (Prince et al, 2021 ). A different study similarly found altered SWRs and PV basket cell (PVBC) activity in the CA1 of 3 month 5xFAD brain slices, with reduced excitatory input to PVBCs during SWRs, and reduced SWR-associated firing of PVBCs (Caccavano et al, 2020 ).…”

Section: Discussionmentioning

confidence: 97%

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Scott

Pelkey

Caccavano

et al. 2022

Front. Synaptic Neurosci.

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Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer’s disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in ex vivo slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from 5xFAD and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and 5xFAD mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aβ deposits/plaque formation. By 6–12 months, 5xFAD animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest 5xFAD animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older 5xFAD mice compared to control, and a reduction of PV and PNNs only in the oldest 5xFAD mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer’s progression.

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Section: Discussionmentioning

confidence: 97%

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Scott

Pelkey

Caccavano

et al. 2022

Front. Synaptic Neurosci.

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“…Another recent study noted PV+ interneuron hyperexictability is an early neuropathological feature in APP/PS1 mice, and showed that chemogenetic inhibition of PV+ interneurons restored excitatory/inhibitory balance and achieved a long-term rescue of hippocampal network and memory deficits, along with reductions in amyloid plaque deposition ( Hijazi et al, 2020 ). Critically, AD is characterized by changes to interneuron-regulated sleep oscillations such as NREM slow waves and spindles, which are an excellent predictor of underlying AD neuropathology ( Kam et al, 2019 ; Winer et al, 2019 ; Caccavano et al, 2020 ; Prince et al, 2021 ; Zhen et al, 2021 ). This phenomenon is also seen in mouse models of AD.…”

Section: Brain State-regulated Interneuron Functions In Brain Disordersmentioning

confidence: 99%

“…This phenomenon is also seen in mouse models of AD. For example, in three recent studies using APP/PS1 and 3xTg-AD mice ( Zhurakovskaya et al, 2019 ; Benthem et al, 2020 ; Prince et al, 2021 ), the occurrence of NREM hippocampal sharp wave-ripples was significantly decreased, as was coupling of oscillations (e.g., sharp waves and slow waves, spindles and slow waves) between hippocampus and cortex. In 5xFAD mice, which typically show a more progressive and severe AD phenotype, altered frequency and amplitude of hippocampal sharp wave-ripples are accompanied by selective reductions of PV+ basket cells’ activity during these oscillations, and corresponding aberrant increases in pyramidal neuron firing ( Caccavano et al, 2020 ).…”

Section: Brain State-regulated Interneuron Functions In Brain Disordersmentioning

confidence: 99%

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

Raven

Aton

2021

Front. Neural Circuits

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Brain states such as arousal and sleep play critical roles in memory encoding, storage, and recall. Recent studies have highlighted the role of engram neurons–populations of neurons activated during learning–in subsequent memory consolidation and recall. These engram populations are generally assumed to be glutamatergic, and the vast majority of data regarding the function of engram neurons have focused on glutamatergic pyramidal or granule cell populations in either the hippocampus, amygdala, or neocortex. Recent data suggest that sleep and wake states differentially regulate the activity and temporal dynamics of engram neurons. Two potential mechanisms for this regulation are either via direct regulation of glutamatergic engram neuron excitability and firing, or via state-dependent effects on interneuron populations–which in turn modulate the activity of glutamatergic engram neurons. Here, we will discuss recent findings related to the roles of interneurons in state-regulated memory processes and synaptic plasticity, and the potential therapeutic implications of understanding these mechanisms.

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“…If the synaptic threads weaken, the web should fade away and memories sink into the oblivion. A recent paper by Prince et al 2 aims to dig into this idea.…”

Section: Commentarymentioning

confidence: 99%

Threaded Structure of a Pathological Oblivion

Prida¹

2021

Epilepsy Curr

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Synapse loss and altered synaptic strength are thought to underlie cognitive impairment in Alzheimer's disease (AD) by disrupting neural activity essential for memory. While synaptic dysfunction in AD has been well characterized in anesthetized animals and in vitro, it remains unknown how synaptic transmission is altered during behavior. By measuring synaptic efficacy as mice navigate in a virtual reality task, we find deficits in interneuron connection strength onto pyramidal cells in hippocampal CA1 in the 5 relevant human familial mutations (5XFAD) of the mouse model of AD. These inhibitory synaptic deficits are most pronounced during sharp-wave ripples (SWRs), network oscillations important for memory that require inhibition. Indeed, 5XFAD mice exhibit fewer and shorter SWRs with impaired place cell reactivation. By showing inhibitory synaptic dysfunction in 5XFAD mice during spatial navigation behavior and suggesting a synaptic mechanism underlying deficits in network activity essential for memory, this work bridges the gap between synaptic and neural activity deficits in AD.

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Alzheimer’s pathology causes impaired inhibitory connections and reactivation of spatial codes during spatial navigation

Abstract: Highlights d 5XFAD mice have weakened inhibitory synaptic efficacy during behavior d Weakened inhibition in 5XFAD mice occurs during sharpwave ripples d 5XFAD mice have fewer and shorter sharp-wave ripples d Place cell reactivation is impaired during the remaining ripples in 5XFAD mice

Cited by 38 publications

References 114 publications

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

Threaded Structure of a Pathological Oblivion

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