Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

Chang, Pishan; Bush, Daniel; Schorge, Stephanie; Good, Mark Andrew; Canonica, Tara; Shing, Nathanael; S, Noy; Wiseman, Frances K.; Burgess, Neil; Tybulewicz, Victor L. J.; Walker, Matthew; Fisher, Elizabeth

doi:10.1101/644849

Cited by 3 publications

(5 citation statements)

References 82 publications

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“…Indeed, reduced spike rates and increased tuning in the β-γ-frequency range are both consistent with increased activity of inhibitory neurons ( Atallah et al, 2012 ; Cardin et al, 2009 ; Chen et al, 2017 ; Sohal et al, 2009 ; Veit et al, 2017 ). The overall LFP power spectra observed in mPFC is similar in both Ts and Eu mice, consistently with a recent report ( Chang et al, 2020 ). However, close examination of stLFP revealed a strong increase in the power of β- and low γ-frequency bands during periods of spiking activity.…”

Section: Discussionsupporting

confidence: 92%

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Martín

Donato

Peixoto

et al. 2020

eLife

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Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

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Section: Discussionsupporting

confidence: 92%

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Martín

Donato

Peixoto

et al. 2020

eLife

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“…An increased hippocampal-mPFC theta coherence was also observed in these animals, which is in agreement with clinical findings showing increased synchrony between neural networks in persons with DS [228,229]. Mouse models of DS also showed altered hippocampal theta-phase modulation of low and high gamma amplitude during rest and behavioral performance [162,163]. Recently, it has been reported that PV basket cells lost their classical fast-spiking phenotype and showed increased excitability in mPFC slices from Ts65Dn mice [164].…”

Section: Electrophysiological Ad-related Phenotypes In Animal Models ...supporting

confidence: 88%

“…Findings from preclinical studies suggest that an early excitation/inhibition imbalance leads to over-inhibition in neural circuits, which may contribute to changes in network activity of DS mouse models [162-164, 226, 227] (Table 1). For example, Dp1Tyb mice showed a general slowing of theta-band oscillations across the hippocampus and medial prefrontal cortex (mPFC), which was associated with slower decision-making in a spontaneous alternation task [162]. An increased hippocampal-mPFC theta coherence was also observed in these animals, which is in agreement with clinical findings showing increased synchrony between neural networks in persons with DS [228,229].…”

Section: Electrophysiological Ad-related Phenotypes In Animal Models ...supporting

confidence: 78%

“…In sum, electrophysiological findings in persons with DS corroborate evidence from studies supporting the well-accepted notion in the AD research community that slowing of brain rhythm may be associated with the level of cognitive deterioration, and hence may serve as a biomarker to predict the onset of dementia [157,161]. Yet, few studies in DS have focused on investigating cross-frequency interactions between different brain rhythms, and much of the existing evidence arises from preclinical findings [162][163][164].…”

Section: Altered Neural Activity Dynamics In Dssupporting

confidence: 73%

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Toward the Identification of Neurophysiological Biomarkers for Alzheimer’s Disease in Down Syndrome: A Potential Role for Cross-Frequency Phase-Amplitude Coupling Analysis

Victorino¹,

Faber²,

Pinheiro³

et al. 2022

Aging and disease

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Cross-frequency coupling (CFC) mechanisms play a central role in brain activity. Pathophysiological mechanisms leading to many brain disorders, such as Alzheimer's disease (AD), may produce unique patterns of brain activity detectable by electroencephalography (EEG). Identifying biomarkers for AD diagnosis is also an ambition among research teams working in Down syndrome (DS), given the increased susceptibility of people with DS to develop early-onset AD (DS-AD).Here, we review accumulating evidence that altered theta-gamma phase-amplitude coupling (PAC) may be one of the earliest EEG signatures of AD, and therefore may serve as an adjuvant tool for detecting cognitive decline in DS-AD. We suggest that this field of research could potentially provide clues to the biophysical mechanisms underlying cognitive dysfunction in DS-AD and generate opportunities for identifying EEG-based biomarkers with diagnostic and prognostic utility in DS-AD.

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“…This constellation of evidence leads to the hypothesis that since input to hippocampus from MS is dysfunctional in DS, hippocampal function in TS animals may be abnormal in ways that parallel the changes in human DS that result in deficits in learning and memory. Recent experiments using mouse models of DS strongly suggest spectral phase abnormalities between the hippocampus and prefrontal cortex, and differences in phase-amplitude coupling between theta and gamma in the hippocampus 47 . In these experiments, we use tetrode-based single-unit electrophysiology to record place cells within CA1 of the hippocampus, co-record hippocampal LFP, and examine changes in spectral coherence within the hippocampus that may underlie the central learning and memory deficits in DS.…”

Section: Introductionmentioning

confidence: 99%

Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome

Heller

Freeburn

Finn

et al. 2020

Preprint

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Down Syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS have shown changes in spectral coherence in the field potentials of hippocampus and regions important for executive function such as prefrontal cortex. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from Medial Septum (MS) to regions such as hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in the Ts65Dn mouse model of DS in comparison to their non-trisomic 2N littermates. We find changes in hippocampal phenomenology that suggest that MS output, which drives theta rhythm in the hippocampus, is strongly altered. Moreover, we find that this change affects the phasic relationship of both CA1 place cells and gamma rhythms to theta. Since the phasic relationship of both of these aspects of hippocampal phenomenology to theta are thought to be critical for the segregation of encoding and retrieval epochs within hippocampus, it is likely that these changes are the neural substrates of the learning and memory deficits seen both in human DS and animal models such as Ts65Dn.

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Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

Abstract: 24 7 These authors contributed equally 25 8 Correspondence: m.walker@ucl.ac.uk 26 27 41 42

Cited by 3 publications

References 82 publications

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Toward the Identification of Neurophysiological Biomarkers for Alzheimer’s Disease in Down Syndrome: A Potential Role for Cross-Frequency Phase-Amplitude Coupling Analysis

Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome

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