Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice

Wu, Qian; Bai, Yang; Li, Wei; Congdon, Erin E.; Liu, Wenke; Yang, Lin; Ji, Changyi; Gan, Wen‐Biao; Sigurdsson, Einar M.

doi:10.1016/j.nbd.2020.105165

Cited by 9 publications

(36 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous study from our group showed that a tau monoclonal antibody 4E6 that targets phosphorylated tau-Ser396/Ser404 (pS396/S404) partially restored abnormal Ca 2+ activity and decreases pathological tau in 10-12 month old JNPL3 mice 1 . The improvement in Ca 2+ activity correlated with decreased soluble pathological tau 1 . Another tau mAb, 8B2, also targets pS396/S404, but has a different binding profile than 4E6 17 .…”

Section: Reduced Pathological Tau and Gliosis In 6 Month Old Jnpl3 Mi...mentioning

confidence: 87%

See 1 more Smart Citation

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

Ji,

Yang,

Eleish

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

We previously reported altered neuronal Ca2+dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca2+activity profile and decreasing pathological tau in these mice1. Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models.In this study, we first performed in vivo two-photon Ca2+imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca2+transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca2+transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age.A more detailed populational analysis of the pattern of Ca2+activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca2+profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region.Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca2+activity deficits but failed to rescue altered network changes.Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies.HighlightsLayer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy.Altered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running.Layer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions.Acute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction.

show abstract

Section: Reduced Pathological Tau and Gliosis In 6 Month Old Jnpl3 Mi...mentioning

confidence: 87%

“…Previous studies have reported abnormal neuronal function in tauopathy mouse models using invivo two photon Ca 2+ imaging 1,5,6 . Two of them reported a decrease in neuronal activity, as measured by Ca 2+ transient frequency and total Ca 2+ activity in two different tauopathy mouse models under anesthesia or quite wakefulness 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

Ji,

Yang,

Eleish

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, three points merit discussion. First, both hyper and hypo activity have been suggested in tauopathy (Perez et al, 2013; Wu et al, 2021). Further, despite consistent degradation of cognition, altered activity is not observed in all NDDs.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperactivity is widely reported in amyloidosis (Keskin et al, 2017; Lerdkrai et al, 2018; Grienberger et al, 2012), although it may be constrained to a subset of cells (Busche et al, 2008). Second, results indicating hyper/hypo activity rely on relatively brief recordings (as little as five minutes), and are often tied to neurophysiological events and behaviors, such as sharp wave ripples (Prince et al, 2021), seizures (Palop et al, 2007), and running (Wu et al, 2021). Third, indirect measures of action potential generation, such as calcium imaging, are differentially sensitive to dissimilar patterns of neuronal activity (Wei et al, 2020; Huang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons

McGregor,

Farris,

Ensley

et al. 2023

Preprint

View full text Add to dashboard Cite

The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network's nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal's genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.

show abstract

“…It thus appears as if α‐amylase is not crucial for neuronal activity per se , but a lack of the enzyme induces an alteration which may be pathological. From this perspective, it is interesting that a recent study demonstrates lowered amplitude of intracellular calcium and higher frequency of calcium oscillations in motor cortex neurons of transgenic JNPL3 tauopathy mice (Wu et al, 2021 ). The calcium dyshomeostasis in these mice was linked to a selective downregulation of AMPA receptors, which regulates formation of LTP via postsynaptic abundance (Diering & Huganir, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

et al. 2021

View full text Add to dashboard Cite

Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha‐amylase (α‐amylase), a glycogen degradation enzyme, located within synaptic‐like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of α‐amylase perform better on the episodic memory test. We reported that neuronal α‐amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in α‐amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α‐amylase concentrations in oligomer amyloid beta 42 (Aβ42) stimulated SH‐SY5Y cells and neurons derived from human‐induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α‐amylase production and activity, induced by siRNA and α‐amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH‐SY5Y cells. Both oligomer Aβ42 stimulated SH‐SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α‐amylase within synapses of isolated primary neurons and show that inhibition of α‐amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α‐amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α‐amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients.

show abstract

Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice

Cited by 9 publications

References 45 publications

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons

Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

Contact Info

Product

Resources

About