EXCITATORY TARGETS, INHIBITORY CONSEQUENCES: HOW AMYLOID-Β OLIGOMERS TIP THE SCALES OF NETWORK E/I BALANCE DURING EARLY ALZHEIMER’S DISEASE​​​​​

Early Alzheimer’s disease (AD) is marked by a gradual accumulation of amyloid‐β oligomers (AβOs) that disrupt synaptic function and induce hyperexcitability in neuronal networks. This disruption of brain activity occurs long before measurable cognitive impairments emerge, yet the underlying mechanism remains unresolved.
Our previous work demonstrated that 24‐hour exposure to AβOs impair synaptic transmission at GABAergic synapses in hippocampal slices. To investigate the differential vulnerability of synapses to AβOs, we now employed live synaptotagmin‐1 antibody uptake assays, and genetically encoded sensors for glutamate (iGluSnFR3) and GABA (iGABASnFR2) with live-cell imaging in primary hippocampal neurons.
We found that AβO exposure induced network hyperexcitability by selectively disrupting synaptic vesicle (SV) turnover at inhibitory boutons. These presynaptic changes resulted from a reduction in release probability at GABAergic synapses, while glutamatergic boutons appeared functionally unaffected.
To assess whether selective vulnerability of GABAergic synapses could be explained by preferential AβO binding, we performed immunohistochemistry experiments. Surprisingly, we observed that AβOs did not accumulate on GABAergic neurons; instead, they primarily clustered at synaptic and extrasynaptic locations on the membranes of glutamatergic neurons. We hypothesized that during early AD, AβOs accumulate on excitatory neurons, triggering indirect signaling events leading to the impairment of GABA release at inhibitory synapses.
Consistent with this model, we found that AβOs bind to postsynaptic mGluR5 at excitatory neurons. We are currently investigating if this enhances endocannabinoid production and retrograde activation of presynaptic cannabinoid receptors at inhibitory synapses, providing a mechanistic explanation for E/I imbalance in early AD.