Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile.
The NMDA receptor is thought to play a central role in some forms of neuronal plasticity, including the induction of long-term potentiation. NMDA receptor hypofunction can result in mnemonic impairment and has been implicated in the cognitive symptoms of schizophrenia. The activity of NMDA receptors is controlled by its endogenous coagonist glycine, and a local elevation of glycine levels is expected to enhance NMDA receptor function. Here, we achieved this by the generation of a novel mouse line (CamKIIalphaCre;Glyt1tm1.2fl/fl) with a neuron and forebrain selective disruption of glycine transporter 1 (GlyT1). The mutation led to a significant reduction of GlyT1 and a corresponding reduction of glycine reuptake in forebrain samples, without affecting NMDA receptor expression. NMDA (but not AMPA) receptor-evoked EPSCs recorded in hippocampal slices of mutant mice were 2.5 times of those recorded in littermate controls, suggesting that neuronal GlyT1 normally assumes a specific role in the regulation of NMDA receptor responses. Concomitantly, the mutants were less responsive to phencyclidine than controls. The mutation enhanced aversive Pavlovian conditioning without affecting spontaneous anxiety-like behavior in the elevated plus maze and augmented a form of attentional learning called latent inhibition in three different experimental paradigms: conditioned freezing, conditioned active avoidance, conditioned taste aversion. The CamKIIalphaCre;Glyt1tm1.2fl/fl mouse model thus suggests that augmentation of forebrain neuronal glycine transmission is promnesic and may also offer an effective therapeutic intervention against the cognitive and attentional impairments characteristic of schizophrenia.
Yee
Benjamin K
BK
Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology, 8603 Schwerzenbach, Switzerland.
Balic
Ela
E
Singer
Philipp
P
Schwerdel
Cornelia
C
Grampp
Thomas
T
Gabernet
Laetitia
L
Knuesel
Irene
I
Benke
Dietmar
D
Feldon
Joram
J
Mohler
Hanns
H
Boison
Detlev
D
D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics; D001288:Attention / Q000502:physiology; D001362:Avoidance Learning / Q000502:physiology; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D005998:Glycine / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics*; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D010641:Phenotype; D016548:Prosencephalon / Q000254:growth & development* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009435:Synaptic Transmission / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493267:Slc6a9 protein, mouse; D005998:Glycine