Towards a critical test of the synaptic plasticity and memory hypothesis

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How memory is stored in the brain is unknown. The dominant synaptic plasticity and memory (SPM) hypothesis asserts that memory is stored by functional modifications induced by learning at a subset of the synapses of the neurons that are activated to encode the learning experience. This predicts permanent memory erasure is caused by post-learning inhibition of a molecular synaptic plasticity maintenence mechanism that is necessary for persistent storage of the long-term memory. Indeed, erasure of a variety of memories has been demonstrated by intracranial ZIP administration. ZIP inhibits the kinase activity of atypical PKCs, PKMζ and PKCι/λ, both of which can be persistently upregulated following memory acquisition. PKMζ is both necessary and sufficient for wildtype late-LTP maintenance, and when the PKMζ gene Prkcz is deleted, PKCι/λ compensates for the loss of PKMζ, becoming necessary for maintaining late-LTP. Intracranial aPKC manipulations erase a variety of long-term memories, but not all, providing crucial support for the foundational SPM hypothesis. However, because the manipulations act generally, affecting cells that may not participate in the memory storage, it is crucial to selectively depotentiate synapses in a memory-associated subset of cells to critically test the SPM hypothesis. Indeed, others have used the fact that memory formation requires protein synthesis to challenge the SPM hypothesis. They demonstrated that post-learning optogenetic stimulation of a context-fear memory-activated subset of hippocampal neurons is sufficient to express the memory, even after an amnesia-producing block of protein synthesis. However, these studies did not critically test the SPM hypothesis because neither hippocampus function, nor the most common N-Methyl-D-Aspartate receptor (NMDAR)- and aPKC-dependent form of LTP in the hippocampus are necessary for context-fear memory, amongst other experimental issues. We propose to critically test the SPM hypothesis using 1) a long-term active place avoidance memory that is sufficient to induce persistent hippocampal synaptic potentiation, and depends on hippocampus PKMζ, both for at least 30 days; 2) optogenetic activation of neurons that is sufficient to express the avoidance memory; and 3) aPKC manipulations that are genetically targeted to the memory-associated subset of cells. We will optogenetically activate a “sufficient-for-memory” subset of the hippocampal neurons that are allocated to encode and recall a specific place memory, after erasing the memory and associated synaptic plasticity by aPKC manipulation of the same cells. We will evaluate if after erasure, optogenetic activation of the memory-associated cells expresses the spatial information in neural discharge and the conditioned avoidance behavior that express the memory. If the optogenetic activation causes memory expression, the SPM hypothesis will require modification, at least as far as it it concerns aPKC-dependent synaptic plasticity and active place avoidance memory.