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

• Published in: Hippocampus Vol. 29; no. 12; pp. 1150 - 1164
• Main Authors: Alcantara‐Gonzalez, David, Villasana‐Salazar, Benjamín, Peña‐Ortega, Fernando
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2019; Wiley Subscription Services, Inc
• Subjects: 4‐aminopyridine; Alzheimer's disease; amyloid beta; Amyloidosis; Cognitive ability; Convulsions & seizures; Epilepsy; Hippocampus; Injection; Latency; Neural networks; Neurodegenerative diseases; oscillations; Seizures; synaptic coupling; Temporal lobe; seizures; 4-aminopyridine; oscillations; amyloid beta; synaptic coupling
• ISSN: 1050-9631; 1098-1063
• DOI: 10.1002/hipo.23129

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.