Impaired long-term depression in P2X3 deficient mice is not associated with a spatial learning deficit.

The hippocampus is a brain region critical for learning and memory processes believed to result from long-lasting changes in the function and structure of synapses. Recent findings suggest that ATP functions as a neurotransmitter or neuromodulator in the mammalian brain, where it activates several different types of ionotropic and G protein-coupled ATP receptors that transduce calcium signals. However, the roles of specific ATP receptors in synaptic plasticity have not been established. Here we show that mice lacking the P2X3 ATP receptor (P2X3KO mice) exhibit abnormalities in hippocampal synaptic plasticity that can be restored by pharmacological modification of calcium-sensitive kinase and phosphatase activities. Calcium imaging studies revealed an attenuated calcium response to ATP in hippocampal neurons from P2X3KO mice. Basal synaptic transmission, paired-pulse facilitation and long-term potentiation are normal at synapses in hippocampal slices from P2X3KO. However, long-term depression is severely impaired at CA1, CA3 and dentate gyrus synapses. Long-term depression can be partially rescued in slices treated with a protein phosphatase 1-2 A activator or by postsynaptic inhibition of calcium/calmodulin-dependent protein kinase II. Despite the deficit in hippocampal long-term depression, P2X3KO mice performed normally in water maze tests of spatial learning, suggesting that long-term depression is not critical for this type of hippocampus-dependent learning and memory.

NMDA antagonist MK-801 impairs acquisition of place strategies, but not their use.

Evidence that NMDA receptors contribute to synaptic plasticity in the hippocampus has stimulated research on their role in behavioral learning and memory. Recent studies indicate that NMDA antagonists decrease use of place strategies by rats in a T-maze task that can be solved using either a "place" or "response" strategy. In the present study, rats were given MK-801 before maze exposure and/or training on this redundant strategy T-maze task. MK-801 did not impair rats' ability to learn the task, but did change the strategies they used on a probe trial administered after learning. MK-801 decreased use of place strategies only when administered before both maze exposure and training; rats given MK-801 only before maze exposure or only before training tended to use place strategies on the probe trial. These results show that MK-801 does not prevent rats from utilizing previously acquired spatial information, but does appear to impair the acquisition of spatial information needed for place strategies.

Involvement of Notch signaling in hippocampal synaptic plasticity.

During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kappa B activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes.