The ryanodine receptor 2 (RyR2) releases calcium from intracellular stores in neurons. In disease, this calcium release is altered, resulting in calcium dyshomeostasis. This can lead to changes in synaptic signaling and intrinsic excitability.

We have examined neuronal excitability in two mouse models that exhibit altered RyR2 function:

• Mice genetically altered to mimic complete phosphorylation or dephosphorylation of RyR2 by protein kinase CK2
• A mouse model of Alzheimer’s disease (AD) with early onset seizures

Ex vivo calcium imaging found that complete phosphorylation of RyR2 by CK2 resulted in neuronal hyperactivity in hippocampal CA1 neurons, however this neuronal hyperactivity was not sufficient to induce seizure susceptibility in vivo.

In the AD model, ex vivo calcium imaging in CA1 neurons of young animals, susceptible to seizures, showed neuronal hyperactivity relative to the wild-type mice. This hyperactivity was prior to the formation of β-amyloid plaques. Parallel continuous EEG recordings found frequency band signatures associated with AD and used machine learning to identify seizures in the EEG recording from these mice.

Ongoing work to examine the role of RyR2 in hyperactive CA1 neurons will also be discussed.