Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity

There is considerable interest in the regulation of sensorimotor gating, since deficits in this process could play a critical role in the symptoms of schizophrenia and other psychiatric disorders. Sensorimotor gating is often studied in humans and rodents using the prepulse inhibition of the acoustic startle response (PPI) model, in which an acoustic prepulse suppresses behavioral output to a startle-inducing stimulus. However, the molecular and neural mechanisms underlying PPI are poorly understood. Here, we show that a regulatory pathway involving protein phosphatase 2A (PP2A), glycogen synthase kinase 3 beta (GSK3 beta), and their downstream target, the M-type potassium channel, regulates PPI. Mice (Mus musculus) carrying a hypomorphic allele of Ppp2r5 delta, encoding a regulatory subunit of PP2A, show attenuated PPI. This PPP2R5 delta reduction increases the phosphorylation of GSK3 beta at serine 9, which inactivates GSK3 beta, indicating that PPP2R5 delta positively regulates GSK3 beta activity in the brain. Consistently, genetic and pharmacological manipulations that reduce GSK3 beta function attenuate PPI. The M-type potassium channel subunit, KCNQ2, is a putative GSK3 beta substrate. Genetic reduction of Kcnq2 also reduces PPI, as does systemic inhibition of M-channels with linopirdine. Importantly, both the GSK3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione (SB216763) and linopirdine reduce PPI when directly infused into the medial prefrontal cortex (mPFC). Whole-cell electrophysiological recordings of mPFC neurons show that SB216763 and linopirdine have similar effects on firing, and GSK3 inhibition occludes the effects of M-channel inhibition. These data support a previously uncharacterized mechanism by which PP2A/GSK3 beta signaling regulates M-type potassium channel activity in the mPFC to modulate sensorimotor gating.