Single amyloid‐beta injection exacerbates 4‐aminopyridine‐induced seizures and changes synaptic coupling in the hippocampus

Abstract

Accumulation of amyloid‐beta (Aβ) in temporal lobe structures, including the hippocampus, is related to a variety of Alzheimer's disease symptoms and seems to be involved in the induction of neural network hyperexcitability and even seizures. Still, a direct evaluation of the pro‐epileptogenic effects of Aβ in vivo, and of the underlying mechanisms, is missing. Thus, we tested whether the intracisternal injection of Aβ modulates 4‐aminopyridine (4AP)‐induced epileptiform activity, hippocampal network function, and its synaptic coupling. When tested 3 weeks after its administration, Aβ (but not its vehicle) reduces the latency for 4AP‐induced seizures, increases the number of generalized seizures, exacerbates the time to fully recover from seizures, and favors seizure‐induced death. These pro‐epileptogenic effects of Aβ correlate with a reduction in the power of the spontaneous hippocampal network activity, involving all frequency bands in vivo and only the theta band (4–10 Hz) in vitro. The pro‐epileptogenic effects of Aβ also correlate with a reduction of the Schaffer‐collateral CA1 synaptic coupling in vitro, which is exacerbated by the sequential bath application of 4‐AP and Aβ. In summary, Aβ produces long‐lasting pro‐epileptic effects that can be due to alterations in the hippocampal circuit, impacting its coordinated network activity and its synaptic efficiency. It is likely that normalizing synaptic coupling and/or coordinated neural network activity (i.e., theta activity) may contribute not only to improve cognitive function in Alzheimer's disease but also to avoid hyperexcitation in conditions of amyloidosis.

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

“…Moreover, Aβ-induced synaptic over-scaling can likely increase the overall excitability of the local neural network that can constitute the substrate for the epileptiform activity associated with the early phases of AD progression [ 21 , 22 ]. The exposure of rodent hippocampal neurons and slides to Aβ oligomers, as well as intracisternal injection of Aβ, is able to elicit pro-epileptogenic changes and to facilitate seizure and synaptic coupling [ 192 , 193 , 194 ], while in the Tg2576 mouse model, which is characterized by a progressive increase in Aβ production and deposition, Aβ oligomers have been demonstrated to affect intrinsic and extrinsic neuronal properties impairing dentate gyrus transmission and lowering the hippocampal seizure threshold [ 62 , 195 , 196 ]. The enhanced epileptic activity observed in the DG of both this mouse model and of oligomer-treated slices appeared to be related with a dysfunction in D1-dopamine(DA) receptor transmission [ 62 ].…”

Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau

“…It further surged the number of generalized seizures, impaired the time for full recovery, and favored seizure-induced death. These pro-epileptogenic effects of Aβ have been correlated with the disruption of normal hippocampal function by affecting the synaptic efficacy and its coordinated network activity [89].…”

Beta-amyloid peptides(1–42) and (1–40) in the cerebrospinal fluid during pregnancy: a prospective observational study

“…In a postmortem study, a lower beta-amyloid load in CSF of patients with Alzheimer’s disease correlated with increased beta-amyloid aggregates in brain parenchyma (Blennow and Zetterberg 2018 ). Interestingly, Alcantara-Gonzalez et al ( 2019 ) found that injection of beta-amyloid could induce seizures in the rat brain. Whether an excess of beta-amyloid peptides in brain parenchyma due to a pathologic production or a clearance defect is causative for seizures in eclampsia is hypothetical and remains to be investigated.…”