Eric Kandel, Columbia University, New York
Nobel Laureate in Physiology or Medicine 2000
Title: Functional Prions and the Maintenance of Memory Storage
March 20, 10.30-11.30
Host: Hugo Lagercrantz
Location: Nobel Forum, Nobelsväg 1
Functional Prions and the Maintenance of Memory Storage
Long-term behavioralsensitization in Aplysiacangiverisetosynapse-specific long-term facilitation in the synapticconnectionsbetween the sensory and the motor neuron. Moreover, thissynapsespecificfacilitationrequires new protein synthesis at the activatedsynapse. Thislocal protein synthesis serves twofunctions: (1) it provides a componentof the mark at the activatedsynapse and therebyconferssynapsespecificity and (2) it stabilizes the synapticgrowthassociatedwith long-term facilitation.
Local protein synthesis at the markedsynapse is controlled by a neuron-specificisoformofcytoplasmicpolyadenylation element binding protein (CPEB). The Aplysia CPEB protein is upregulatedlocally at activatedsynapses. The activation is not needed for the initiation but for the stablemaintenanceof long-term facilitation.
CPEB showedclear prion-like properties. Prion proteins have the unusualcapacitytofoldintotwofunctionallydistinctconformations, oneofwhich is self-perpetuating Moreoverthatconversionof CPEB to a prion-like state in stimulatedsynapseshelpstomaintain long-term synapticchangesassociatedwithmemorystorage.
These studies in Aplysiahaveserved as a backgound fortwo recent and ongoing studies:
1) The search for a CPEB homologs in mammals led to the findingof CPEB-3 in mousewhichregulatesnot bothmaintenance ands reconsolidation. Moreover, CPEB-3 is regulated by the UbiquitinligaseNeurilized
2) Thesearchfoeotherexamplesoffunctionalprions ledto the findingodTIA (T-cell intracellular antigen) cells has alsoclassic prion properties in yeast and serves as part of the cellularresponsetosystemic stress and is activated by paradigms thatleadto post traumatic stress. Usingmicewith knockout of TIAwasfoundto serve as a sex-specificprotectivefactor in PTSD and does so only in femalemice.