Deficits in cognitive function and hippocampal plasticity in GM2/GD2 synthase knockout mice.
In this study, we used GM2/GD2 synthase knockout (GM2/GD2−/−) mice to examine the influence of deficiency in ganglioside “a-pathway” and “b-pathway” on cognitive performances and hippocampal synaptic plasticity. Eight-week-old GM2/GD2−/− male mice showed a longer escape-latency in Morris water maze test and a shorter latency in step-down inhibitory avoidance task than wild-type (WT) mice. Schaffer collateral-CA1 synapses in the hippocampal slices from GM2/GD2−/− mice showed an increase in the slope of EPSPs with reduced paired-pulse facilitation, indicating an enhancement of their presynaptic glutamate release. In GM2/GD2−/− mice, NMDA receptor (NMDAr)-dependent LTP could not be induced by high-frequency (100–200 Hz) tetanus or θ-burst conditioning stimulation (CS), whereas NMDAr-independent LTP was induced by medium-frequency CS (20–50 Hz). The application of mono-sialoganglioside GM1 in the slice from GM2/GD2−/− mice, to specifically recover the a-pathway, prevented the increased presynaptic glutamate release and 20 Hz-LTP induction, whereas it could not rescue the impaired NMDAr-dependent LTP. These findings suggest that b-pathway deficiency impairs cognitive function probably through suppression of NMDAr-dependent LTP, while a-pathway deficiency may facilitate NMDAr-independent LTP through enhancing presynaptic glutamate release. As both of the NMDAr-independent LTP and increased presynaptic glutamate release were sensitive to the blockade of L-type voltage-gated Ca2+ channels (L-VGCC), a-pathway deficiency may affect presynaptic L-VGCC.
Sha
S
Sha
Libin
L
Zhou
Jun
J
Yin
Koga
K
Takamiya
Keiko
K
Furukawa
Koichi
K
Furukawa
Masahiro
M
Sokabe
Ling
L
Chen
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000503:physiopathology*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005677:G(M1) Ganglioside / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D005677:G(M1) Ganglioside; D017350:N-Acetylgalactosaminyltransferases; C000590840:beta-1,4-N-acetyl-galactosaminyl transferase 1, mouse; D002118:Calcium