title: 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.
abstract: 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 (GSK3beta), and their downstream target, the M-type potassium channel, regulates PPI. Mice (Mus musculus) carrying a hypomorphic allele of Ppp2r5delta, encoding a regulatory subunit of PP2A, show attenuated PPI. This PPP2R5delta reduction increases the phosphorylation of GSK3beta at serine 9, which inactivates GSK3beta, indicating that PPP2R5delta positively regulates GSK3beta activity in the brain. Consistently, genetic and pharmacological manipulations that reduce GSK3beta function attenuate PPI. The M-type potassium channel subunit, KCNQ2, is a putative GSK3beta 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/GSK3beta signaling regulates M-type potassium channel activity in the mPFC to modulate sensorimotor gating.
authors.affiliation: Ernest Gallo Clinic and Research Center, Emeryville, California 94608, USA. dkapfhamer@gallo.ucsf.edu
authors.forename: David
authors.initials: D
authors.lastname: Kapfhamer
authors.forename: Karen H
authors.initials: KH
authors.lastname: Berger
authors.forename: F Woodward
authors.initials: FW
authors.lastname: Hopf
authors.forename: Taban
authors.initials: T
authors.lastname: Seif
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heberlein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007266:Inhibition, Psychological; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction
chemical_list: D051658:KCNQ2 Potassium Channel; D015221:Potassium Channels; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C475028:Ppp2r5d protein, mouse; D054648:Protein Phosphatase 2