Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1.
Adaptive purposeful behaviour depends on appropriate modifications of synaptic connectivity that incorporate an organism's past experience. At least some forms of such synaptic plasticity are believed to be mediated by NMDA receptors (NMDARs). Complementary interaction with inhibitory neurotransmission mediated by GABA(A) receptors, and upstream control of the excitability of NMDARs by glycine availability can greatly influence the efficacy of NMDAR mediated neuroplasticity, and thereby exert significant effects on cognition. Memory, selective attention or sensorimotor gating functions can be modified in mice with a reduction of alpha(5)GABA(A) receptors in the hippocampus or a selective deletion of glycine transporter 1 (GlyT1) in the forebrain. Both genetic manipulations altered the formation or persistence of associative links leading to distinct phenotypes on trace conditioning, extinction learning, latent inhibition, working memory, and object recognition. Behavioural assays of latent inhibition, prepulse inhibition, working memory, and sensitivity to psychostimulants in particular suggest that alpha(3) and alpha(5) subunit-containing GABA(A) receptors as well as GlyT1 are potential sites for ameliorating psychotic-like behaviour. Taken together, these results qualify distinct GABA-A receptor subtypes and GlyT1 as molecular targets for the development of a new pharmacology in the treatment of cognitive decline and psychotic symptoms.
Möhler
Hanns
H
University of Zurich and Swiss Federal Institute of Technology, Zurich, Institute of Pharmacology, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. mohler@pharma.uzh.ch
Rudolph
Uwe
U
Boison
Detlev
D
Singer
Philipp
P
Feldon
Joram
J
Yee
Benjamin K
BK
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001245:Association Learning / Q000187:drug effects; D001519:Behavior / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D014151:Anti-Anxiety Agents; D050487:Glycine Plasma Membrane Transport Proteins; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A