Selective weakening of population-coupled synaptic activity in vivo in a mouse model of amyloid-beta pathology
Leire Melgosa-Ecenarro1, Carola I Radulescu1, Nazanin Doostdar1
1UK Dementia Research Institute Centre, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK.
Abstract:
Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in AppNL-G-F mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic structure/function imaging finds reduced density and calcium-mediated activity of GABAergic axonal boutons. Rather than occurring globally, reduced synaptic activity is focused at GABAergic boutons strongly coupled to population activity in the amyloid microenvironment. The selective weakening of population-coupled synaptic activity also occurs in excitatory dendritic spines. Spatial transcriptomics finds parvalbumin-positive inhibitory neurons show differential gene expression associated with downregulated GABAergic synaptic transmission at early stages. We propose that early-stage AD-related synaptic pathophysiology is focused at population-coupled synapses, with molecular measures implicating abnormal synaptic processing as an early-stage feature in parvalbumin-positive interneurons.
Insights
Early Alzheimer's disease (AD) involves synaptic dysfunction, not globally, but specifically at GABAergic synapses linked to neural network activity. This points to abnormal synaptic processing in inhibitory neurons as an early AD feature.
Area of Science:
- Neuroscience
- Alzheimer's Disease Research
- Synaptic Plasticity
Background:
- Synaptic dysfunction is a hallmark of Alzheimer's disease (AD), potentially causing cognitive decline.
- It remains unclear if AD-induced synaptic changes are widespread or localized.
Purpose of the Study:
- To investigate in vivo synaptic dysfunction during early amyloidosis in a mouse model of AD (AppNL-G-F mice).
- To determine the spatial extent and specific synaptic types affected by early-stage AD pathology.
Main Methods:
- In vivo imaging of synaptic structure and function in early-stage AD mouse models.
- Analysis of presynaptic proteins and neuronal calcium-mediated activity.
- Spatial transcriptomics to identify gene expression changes in specific neuronal populations.
Main Results:
- Reduced presynaptic GABAergic proteins and increased calcium activity in neuronal assemblies were observed.
- Synaptic structure/function imaging revealed decreased density and activity of GABAergic axonal boutons.
- Synaptic dysfunction was localized to GABAergic boutons coupled to neuronal activity within the amyloid microenvironment.
- Differential gene expression in parvalbumin-positive interneurons indicated downregulated GABAergic transmission.
Conclusions:
- Early-stage AD synaptic pathophysiology is not global but focused on population-coupled synapses.
- Abnormal synaptic processing in parvalbumin-positive interneurons is an early feature of AD.
- Findings highlight the specific vulnerability of inhibitory synapses in early AD pathogenesis.
