Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model

Abstract

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [ 11 C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[ 11 C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus

“…Interestingly, the frontotemporal dementia (FTD)-associated hTau V337M mutation was recently shown to increase neuronal excitability in human induced pluripotent stem cell–derived neurons by impacting AIS activity-dependent plasticity [ 62 ]. These data agree with several reports showing human mutant tau variants are associated with network hyperexcitability in mouse models [ 63 – 67 ]. It is possible then that detection of hTau-mediated effects on neuronal activity is partly dependent on the sensitivity of the assays used to measure them, the type of tau being studied (e.g., P301L, V337M, etc) and the degree of pathological severity in the chosen model system.…”

Dynamic alterations in the central glutamatergic status following food and glucose intake: in vivo multimodal assessments in humans and animal models

“…These diet-related physiological oscillations of tonic neuronal activities could become deteriorated in a diseased condition, as altered mGluR5 availability was shown to emerge in diverse neuropsychiatric disorders. 48 – 52 A murine model of neurodegenerative diseases also exhibited declines of mGluR5 radioligand binding in our recent PET experiments. 52 We therefore postulate that glucose-induced increase and fasting-induced decrease of ( E )-[ 11 C]ABP688 binding can be dysregulated at a prodromal stage of these illnesses, which might offer biological tests to assist the clinical diagnosis.…”

“… 48 – 52 A murine model of neurodegenerative diseases also exhibited declines of mGluR5 radioligand binding in our recent PET experiments. 52 We therefore postulate that glucose-induced increase and fasting-induced decrease of ( E )-[ 11 C]ABP688 binding can be dysregulated at a prodromal stage of these illnesses, which might offer biological tests to assist the clinical diagnosis.…”

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…Another informative use of microPET is to probe changes in excitatory and inhibitory balance throughout the brain, which is thought to be disrupted in various neurodegenerative disorders ( Hynd et al, 2004 ; King et al, 2016 ). In the rTg4510 mouse tauopathy model, 11C-flumazenil (tracer for GABAA benzodiazepine receptors) binding was reduced beginning at 2 months of age, prior to frank neurodegeneration ( Shimojo et al, 2020 ). Similar decreases in 11C-flumazenil binding are noted in early AD patients ( Pascual et al, 2012 ).…”