Receptors and memory: Dr. Rick Huganir’s BCMB Friday Seminar

Dr. Rick Huganir.
(Image reproduced from Department of Neuroscience website)

How do synaptic connections, made of short-lived proteins, last for the duration of a human life? That’s the question Rick Huganir, chair of the Neuroscience department, used to frame his talk, the third in this year’s BCMB Friday Seminar series. Dr. Huganir spoke on “Regulation of receptors, synapses and memory,” focusing on the regulation of AMPARs, excitatory glutamate receptors which mediate about 70% of electrical activity in the brain. Modifications to either the number or the activity of AMPARs at individual synapses can affect how information flows through neural circuits. Trafficking can add or subtract AMPARs to the postsynaptic milieu, while each receptor has dozens of phosphorylation sites that regulate activity, with phosphorylation potentially lasting for the lifetime of a receptor. However, a receptor’s lifetime is, as Dr. Huganir put it, “not [long] enough to solve the problem of a ninety-year-old woman remembering her childhood.” So, how does the increased sensitivity of a strengthened synapse last for any longer than the set of receptors that was around when the initial strengthening stimulus took place? Dr. Huganir’s talk broke down into three connected stories of molecular sleuthing in search of a “very local, self-sustaining mechanism” for tagging neurotransmitter receptors in the long term.

The first section was a story about uncovering the role of a protein involved in AMPAR trafficking. Kibra, which was named for its expression in kidney and brain, was linked to memory both by its high expression in memory-associated brain regions, and by the fact that SNPs in the gene correlate with human performance in memory tasks. Dr. Huganir’s lab showed that kibra associates with the AMPAR complex, and binds to Pick1, a protein the lab had previously shown to be involved in AMPAR endocytosis and recycling. Overexpression of kibra reduces the number of AMPAR components at the synapse, and conditional knockout mice are slower to learn and worse at retaining information.

Continuing the theme of receptor trafficking, the next section dealt with live-animal imaging of such trafficking, to address when and how AMPARs are introduced to the postsynaptic membrane in a live and behaving brain. These studies used an AMPAR subunit tagged with pHlourin, a pH-sensitive fluorescent protein, whose fluorescence is quenched by the acidic environment of the endocytic vesicle, but recovers once such a vesicle fuses to the postsynaptic membrane. In mice expressing this tagged AMPAR subunit, the lab was able to track receptor trafficking in response to whisker deflection, a physiological stimulus which they used because it is compatible with anesthetized and immobilized mice.

The latest-breaking and most controversial of the three stories, recently published in Nature, dealt with a protein kinase that was until now believed to be a key to memory formation. Kinase regulatory circuits are strong suspects for synaptic strengthening because they last longer than individual receptors, and so may modulate many “generations” of receptors. There is a peptide drug called ZIPtide that, if injected into a mouse’s brain after training, prevents memory formation; this peptide also weakly inhibits the kinase PKM zeta. This finding led to great interest in PKM zeta and its potential role in memory formation. However, recently the Huganir lab, along with Robert Messing’s lab from UCSF, demonstrated that a PKM zeta knockout mouse shows no memory deficits. ZIPtide still successfully reverses memory formation in this mouse; Dr. Huganir pointed out that it’s “not a very good drug” because of its promiscuity between protein kinase C family members, and for that matter, different types of memory formation. If there is a single kinase necessary and sufficient to form new memories, it remains unidentified.

The next BCMB Friday seminar, given by Dr. Gerald Hart of the Biological Chemistry department, will happen today, Friday, February 15, at 3 PM. Join us for more exciting science and a post-lecture happy hour!


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