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. © 2013 Wiley Periodicals, Inc.