Piccolo knockdown-induced impairments of spatial learning and long-term potentiation in the hippocampal CA1 region

Neurotransmitter release is regulated at a specific site in nerve terminals called the "active zone", which is composed of various cytomatrix proteins such as Piccolo (also known as Aczonin) and Bassoon. These proteins share regions of high sequence similarity and have very high molecular weights (>400 kDa). Since Piccolo knockout mice have not yet been established, the role of Piccolo in the neuronal system remains unclear. In this study, we investigated the effects of Piccolo antisense oligonucleotide injected into the ventricle on hippocampal long-term potentiation (LTP) and learning and memory assessed with the novel object recognition test and the Morris water maze test. There was no significant difference in cognitive memory between Piccolo antisense-treated and vehicle- or sense-treated mice; however, spatial learning in Piccolo antisense-treated mice was impaired but not in sense- or vehicle-treated mice. Next, we investigated LTP formation in these groups in area CA1 and dentate gyrus of the same hippocampal slices. The magnitude of LTP in Piccolo antisense-treated mice was significantly lower than in sense- or vehicle-treated mice, with no change in basal level. Moreover, the level of high K⁺-induced glutamate release in the antisense-treated mice was significantly lower than in sense-treated mice. Taken together, these results indicate that Piccolo plays a pivotal role in synaptic plasticity in area CA1 and in hippocampus-dependent learning in mice, and that the extracellular levels of glutamate in the hippocampus under stimulated conditions are controlled by Piccolo.