Institutt for biomedisin

Guest lecture by Professor Todd Sacktor

Memory and Theseus’ Ship: KIBRA maintains LTP and long-term memory by perpetually targeting PKMzeta


Professor Todd Sacktor
State University of New York Downstate Medical Center, USA

Persistently active molecules store long-term memory by sustaining potentiation of activated synapses in neural networks. But how activated synapses continually target these molecules remains unclear. The autonomously active PKC isoform, PKMzeta, maintains potentiation exclusively at activated synapses in the synaptic model of memory, long-term potentiation (LTP). However, LTP induction, like memory formation, increases the synthesis of PKMzeta widely in neurons. We now show that KIBRA (kidney and brain expressed protein/WWC1), a postsynaptic scaffolding protein genetically linked to human memory performance, continually anchors PKMzeta function to activated synapses. Synaptic activation drives KIBRA and PKMzeta to postsynaptic sites, where they maintain as complexes in late-LTP. To test the function of this persistent KIBRA-PKMzeta coupling, we decoupled the molecules using antagonists of KIBRA-binding in PKMzeta and, conversely, PKMzeta-binding in KIBRA. Neither decoupling agent measurably affects basal synaptic transmission. However, both reverse established late-LTP. Therefore, KIBRA targets PKMzeta action exclusively at activated synapses. Both agents disrupt maintenance of spatial memories. The zeta-antagonist does not disrupt compensatory PKMzeta-independent maintenance mechanisms in PKMzeta-knockout mice, thus controlling for off-target effects. Therefore, two persistent processes sustain LTP and long-term memory: 1) synaptic potentiation by PKMzeta, and 2) anchoring of this action to activated synapses by KIBRA.

Host: Clive Bramham (clive.bramham@uib.no)