R e s e a R c h a R t i c l e3

SummaryPhysical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer’s disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission.

Long-term potentiation (LTP) is a cellular correlate for memory formation, which requires the dynamic changes of the actin cytoskeleton. As shown by others, the polymerization of the actin network is important for early stages of LTP. Here, we investigated the role of actin dynamics in synaptic tagging and particularly in the induction of protein synthesis-dependent late-LTP in the CA1 region in hippocampal slices in vitro. We found that the inhibition of actin polymerization affects protein synthesis-independent early-LTP, prevents late-LTP, and interferes with synaptic tagging in apical dendrites of hippocampal CA1. The transformation of early-LTP into late-LTP was blocked by the application of the structurally different actin polymerization inhibitors latrunculin A or cytochalasin D. We suggest that the actin network is required for early "housekeeping" processes to induce and maintain early-LTP. Furthermore, inhibition of actin dynamics negatively interacts with the setting of the synaptic tagging complex. We propose actin as a further tag-specific molecule in apical CA1 dendrites where it is directly involved in the tagging/capturing machinery. Consequently, inhibition of the actin network prevents the interaction of tagging complexes with plasticity-related proteins. This results in the prevention of late-LTP by inhibition of the actin network during LTP induction.

Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.

Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer’s disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1—a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT—on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer’s disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.