19958
Regulation of Seizure Susceptibility in Shank3 Deficiency
Objectives: Our aim was to investigate how the autism-related mutation in Shank3 in rodents affects the seizure sensitivity, and to identify the underlying signaling mechanism/s in the regulation of differentially induced seizure susceptibility by Shank3.
Methods: Seizure threshold differences was assessed in Shank3-deficient mouse and rat models using a GABA antagonist (pentilenetetrazol, PTZ), a glutamatergic agonist (kainic acid), electrical stimulation, sound, or hyperthermia to induce seizures. Extracellular and whole-cell recordings of pyramidal cells in hippocampal slices before or during application of relevant seizure induction protocols were used to identify if excitatory and inhibitory transmission is affected differentially with different seizure induction protocols.
Results: Reduced Shank3 levels dramatically affect seizure susceptibility induced by PTZ but not kainic acid or sound. PTZ-induced seizure threshold is significantly increased in Shank3 deficient mice, as well as in Shank3-deficient rats with a similar mutation. Electrophysiological recordings of spontaneous postsynaptic potentials revealed that GABAergic transmission is reduced in Shank3-deficient mice. Additionally, after application of another seizure induction condition, high temperature, to hippocampal slices, hyperthermia-induced synaptic depression is reduced in Shank3-deficient mice.
Conclusions: Our results show that Shank3 deficiency may regulate the inhibitory/excitatory balance and modify the risk for seizures differentially with different induction protocols. Differences in the response to seizure-induction protocols may be due to changes in different molecular targets or differential modulation of overlapping molecular pathways. Ongoing experiments using electrical stimulation and hyperthermia as additional seizure induction protocols will build a more complete model to understand the seizure susceptibility in animal models of PMS. Identification of underlying mechanisms will also help for the development of therapies that are more effective in susceptible individuals by interfering with the processes underlying epilepsy.