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What would Robert Frost have done if his diverging roads ultimately led to the same destination? Some signaling molecules are important in several pathways, which presumably mediate different physiological endpoints. However, Lubin and Sweatt report that both pathways activated by inhibitor kappa B (I
B) kinase (IKK) are important in regulating associative memory in a recent article in Neuron.
The transcription factor nuclear-factor kappa B (NF-B) is important in synaptic plasticity and memory. IB binds NF-B, preventing its entry into the nucleus and blocking its ability to bind DNA. The IKK complex, including the catalytic subunits IKK
and IKK
and the regulatory subunit IKK
, phosphorylates IB, marking it for degradation. Therefore, IKK releases NF-B, allowing it to bind B promoter elements and induce transcription. The IB pathway also regulates chromatin structure, which is important in memory. IB interacts with histone deacetylases and IKK induces histone phosphorylation. The authors aimed to determine which of these pathways is important in memory.
Mice freeze with fear when re-exposed to a chamber in which they have been shocked. The authors treated mice with the NF-B pathway inhibitor diethyl-dithiocarbamate (DDTC) immediately after re-exposure to the shock chamber. Days later, the shock context induced less freezing behavior in DDTC- than in vehicle-treated mice. In the hippocampus, DDTC also reduced IKK phosphorylation, the DNA-binding capacity of NF-B, and histone H3 phosphorylation relative to vehicle treatment. Relative to baseline, IKK phosphorylation and NF-B-DNA binding activity increased only after context re-exposure, suggesting that the NF-B pathway is specifically involved in memory recall.
Directly inhibiting IKK with sulfasalazine reduced context-dependent freezing, IKK phosphorylation, NF-B-DNA binding and the phosphorylation and acetylation of histone H3, suggesting that the IKK complex may mediate NF-B pathway's role in memory recall. Does IKK regulate memory and histone H3 directly or through NF-B? SN50, which inhibits the association of NF-B and B DNA promoter elements, reduced context-dependent freezing but did not affect histone H3 phosphorylation and acetylation, suggesting that NF-B is important in memory but not chromatin structure and that IKK regulates chromatin structure independently of NF-B.
Is the IKK-mediated alteration in chromatin important in memory? Zif268 is an immediate early gene important in associative memory. Relative to baseline, the acetylation and phosphorylation of histone H3 associated with Zif268 increased following re-exposure to the shock context, and this increase was blocked by DDTC. The HDAC inhibitor sodium butyrate rescued the DDTC-induced reduction in context-dependent freezing, suggesting that the NF-B pathway regulates memory through histone acetylation.
Therefore both NF-B-DNA binding and histone acetylation are important in memory reconsolidation. Why would both pathways be involved in memory? According to the authors, although NF-B may specifically be important in memory, IKK's induction of histone acetylation may open up DNA to allow the binding of multiple transcription factors.
