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Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony.

ABSTRACT: The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of these cells. Tau ablation reduces the excitatory inputs to inhibitory neurons, increases the excitability of these cells, and structurally alters their axon initial segments (AISs). In primary neuronal cultures subjected to prolonged overstimulation, tau ablation diminishes the homeostatic response of AISs in inhibitory neurons, promotes inhibition, and suppresses hypersynchrony. Together, these differential alterations in excitatory and inhibitory neurons help explain how tau reduction prevents network hypersynchrony and counteracts brain disorders causing abnormally increased E/I ratios.

SUBMITTER: Chang CW

PROVIDER: S-EPMC8648275 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony.

Chang Che-Wei CW Evans Mark D MD Yu Xinxing X Yu Gui-Qiu GQ Mucke Lennart L

Cell reports 20211001 3

The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of ...[more]

PMID: 34686344

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Project description:ObjectivesPersistent oscillating vertigo that occurs after entrainment to periodic motion is known as Mal de Débarquement Syndrome (MdDS). Down-modulation of this oscillating vertigo is associated with reduction in long-range resting-state functional connectivity between fronto-parieto-occipital regions. In order to determine the association between this oscillating vertigo and hypersynchrony as measured by the auditory steady-state response (ASSR), we investigated the differences in ASSR between individuals with MdDS and healthy controls as well as the change in ASSR in individuals with MdDS before and after treatment with transcranial alternating current stimulation (tACS).Materials and methodsIndividuals with treatment refractory MdDS lasting at least six months received single administrations of fronto-parieto-occipital tACS in an "n-of-1" double-blind randomized design: alpha-frequency in-phase, alpha-frequency antiphase, and gamma frequency antiphase control. The treatment protocol that led to the most acute reduction in symptoms and improved balance was administered for 10-12 sessions given over three days (each session 20-min at 2-4 mA).ResultsTwenty-four individuals with MdDS participated (mean age 53.0 ± 11.8 years [range: 22-66 years, median: 57.0 years]; mean duration of illness 38.6 ± 53.4 months [range: 6-240 months, median: 18.0 months]). Individuals with MdDS had elevated ASSR compared to healthy controls at baseline (t11 = 5.95, p < 0.001). There was a significant decrease in the 40 Hz-ASSR response between responders compared to nonresponders to tACS (t-test, t15 = -2.26, p = 0.04). Both in-phase and anti-phase alpha tACS lead to symptom improvement but only antiphase alpha-tACS led to a significant decrease of 40 Hz-ASSR (t-test, t12 = -9.6, p < 0.001).ConclusionsOur findings suggest that tACS has the potential to reduce network-level hypersynchrony and pathological susceptibility to entrainment by sensory input. To the best of our knowledge, this is the first successful demonstration of desynchronization by noninvasive brain stimulation leading to reduced vertigo. Other disease states associated with pathological functional coupling of neuronal networks may similarly benefit from this novel approach.

Project description:Background and purposePerampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored.Experimental approachThe mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling.Key resultsApplication of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant.Conclusion and implicationsIctogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

Project description:Our study aims to investigate if the ratios proposed by Insall-Salvati and Caton-Deschamps follow the theory of normal distribution levels in a healthy population. 434 skeletal mature, healthy knees were obtained from a CT-scan-based modelling system (SOMA). Patellae height ratios were measured using the Insall-Salvati ratio and the Caton-Deschamps index. The patella height ratios of the sample population were plotted on a quantile plot and diagnosed as patella alta, baja or normal using the original ratio definitions. The study population patella height values at the 95th, 98th and 5th centiles were identified and compared to those described as alta or baja by Insall-Salvati and Caton-Deschamps. This meant that if the patient had patella alta, this would be defined as a ratio of ≥ 1.2 and hypothesised that this would align at the 98th centile of the study population, whilst if diagnosed as patella baja (≤ 0.74), this should align at the 5th centile of the population. The inter-rater reliability of both ratios was calculated using kappa statistics. Two authors made all calculations and compared them for consistency using the intraclass correlation coefficient. For the Insall-Salvati ratio, the study population's value at the 98th centile was equivalent to what Insall-Salvati describes as alta, a ratio of ≥ 1.2. In the study population, patients are overdiagnosed if using the Insall-Salvati ratio as patella baja ≤ 0.74, as the value at the 5th centile in the study population was 0.59. Using the Caton-Deschamps index, the 95th centile was 1.3, higher than the patella alta ratio determined by Caton as a ratio ≥ 1.2. Using Caton-Deschamps, patients are being underdiagnosed if utilising a patella baja ratio of ≤ 0.6. In our population, the 5th centile was 0.75. The two ratios had a kappa coefficient of 0.01, which indicates poor inter-rater reliability. Depending on the ratio used, caton-Deschamps and Insall-Salvati ratios diagnose patients as alta or baja differently. The current patella height ratios have originated from very small, select population samples. The future of patella height discussion should begin with data representing large populations. Then, we can discuss the upper and lower limits of abnormality.

Project description:A key feature of excitatory synapses is the existence of subsynaptic protein nanoclusters whose precise alignment across the cleft in a trans-synaptic nanocolumn influences the strength of synaptic transmission. However, whether nanocolumn properties vary between excitatory synapses functioning in different cellular contexts is unknown. We used a combination of confocal and DNA-PAINT super-resolution microscopy to directly compare the organization of shared scaffold proteins at two important excitatory synapses - those forming onto excitatory principal neurons (Ex→Ex synapses) and those forming onto parvalbumin-expressing interneurons (Ex→PV synapses). As in Ex→Ex synapses, we find that in Ex→PV synapses presynaptic Munc13-1 and postsynaptic PSD-95 both form nanoclusters that demonstrate alignment, underscoring synaptic nanostructure and the trans-synaptic nanocolumn as conserved organizational principles of excitatory synapses. Despite the general conservation of these features, we observed specific differences in the characteristics of pre- and postsynaptic Ex→PV nanostructure. Ex→PV synapses contained larger PSDs with fewer PSD-95 NCs when accounting for size than Ex→Ex synapses. Furthermore, the PSD-95 NCs were larger and denser. The identity of the postsynaptic cell also had a retrograde impact on Munc13-1 organization, as Ex→PV synapses hosted larger Munc13-1 puncta that contained less dense but larger and more numerous Munc13-1 NCs. Moreover, we measured the spatial variability of transsynaptic alignment in these synapse types, revealing protein alignment in Ex→PV synapses over a distinct range of distances compared to Ex→Ex synapses. We conclude that while general principles of nanostructure and alignment are shared, cell-specific elements of nanodomain organization likely contribute to functional diversity of excitatory synapses. Understanding the rules of synapse nanodomain assembly, which themselves are cell-type specific, will be essential for illuminating brain network dynamics.

Dataset Information

Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony.

Publications

Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony.

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