Changes in neural network homeostasis trigger neuropsychiatric symptoms
16.01.2014
Winkelmann A, Maggio N, Eller J, Caliskan G, Semtner M, Häussler U, Jüttner R, Dugladze T, Smolinsky B, Kowalczyk S, Chronowska E, Schwarz G, Rathjen FG, Rechavi G, Haas CA, Kulik A, Gloveli T, Heinemann U, Meier JC.
J Clin Invest. 2014;124(2):696-711
The mechanisms that promote disease-causing neural network of dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the glycine receptor (GlyR) that is found in hippocampectomies from patiens with temporal lobe epilepsy. Expression of GlyRs in terminals of glutamatergic cells or in PV+ interneurons altered neural network excitability. The increased excitability associated with GlyR expression in glutamatergic neurons resulted in epileptiform discharge, which provoked cognitive dysfunction and memory deficit without affecting synaptic plasticity. Decreased network excitability due to GlyR expression in PV+ interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or memory. This model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior. Our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.
