title: Chronically saturating levels of endogenous glycine disrupt glutamatergic neurotransmission and enhance synaptogenesis in the CA1 region of mouse hippocampus.
abstract: Glycine serves a dual role in neurotransmission. It is the primary inhibitory neurotransmitter in the spinal cord and brain stem and is also an obligatory coagonist at the excitatory glutamate, N-methyl-D-aspartate receptor (NMDAR). Therefore, the postsynaptic action of glycine should be strongly regulated to maintain a balance between its inhibitory and excitatory inputs. The glycine concentration at the synapse is tightly regulated by two types of glycine transporters, GlyT1 and GlyT2, located on nerve terminals or astrocytes. Genetic studies demonstrated that homozygous (GlyT1-/-) newborn mice display severe sensorimotor deficits characterized by lethargy, hypotonia, and hyporesponsivity to tactile stimuli and ultimately die in their first postnatal day. These symptoms are similar to those associated with the human disease glycine encephalopathy in which there is a high level of glycine in cerebrospinal fluid of affected individuals. The purpose of this investigation is to determine the impact of chronically high concentrations of endogenous glycine on glutamatergic neurotransmission during postnatal development using an in vivo mouse model (GlyT1+/-). The results of our study indicate the following; that compared with wild-type mice, CA1 pyramidal neurons from mutants display significant disruptions in hippocampal glutamatergic neurotransmission, as suggested by a faster kinetic of NMDAR excitatory postsynaptic currents, a lower reduction of the amplitude of NMDAR excitatory postsynaptic currents by ifenprodil, no difference in protein expression for NR2A and NR2B but a higher protein expression for PSD-95, an increase in their number of synapses and finally, enhanced neuronal excitability.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Wafae
authors.initials: W
authors.lastname: Bakkar
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Ma
authors.forename: Mohan
authors.initials: M
authors.lastname: Pabba
authors.forename: Pamela
authors.initials: P
authors.lastname: Khacho
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Emilie
authors.initials: E
authors.lastname: Muller
authors.forename: Marzia
authors.initials: M
authors.lastname: Martina
authors.forename: Richard
authors.initials: R
authors.lastname: Bergeron
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D005998:Glycine / Q000378:metabolism* / Q000502:physiology; D050487:Glycine Plasma Membrane Transport Proteins / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; C493267:Slc6a9 protein, mouse; D018698:Glutamic Acid; D005998:Glycine