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Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10192-7. doi: 10.1073/pnas.1609957113. Epub 2016 Aug 22.

Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus.

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Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 353-0198, Japan;
Senior Advisor's Office, RIKEN Brain Science Institute, Wako, Saitama 353-0198, Japan


Long-term depression (LTD) of synaptic transmission from parallel fibers (PFs) to a Purkinje cell (PC) in the cerebellum has been considered to be a core mechanism of motor learning. Recently, however, discrepancies between LTD and motor learning have been reported in mice with a mutation that targeted the expression of PF-PC LTD by blocking AMPA-subtype glutamate receptor internalization regulated via the phosphorylation of AMPA receptors. In these mice, motor learning behavior was normal, but no PF-PC LTD was observed. We reexamined slices obtained from these GluA2 K882A and GluA2 Δ7 knockin mutants at 3-6 mo of age. The conventional protocols of stimulation did not induce LTD in these mutant mice, as previously reported, but surprisingly, LTD was induced using certain modified protocols. Such modifications involved increases in the number of PF stimulation (from one to two or five), replacement of climbing fiber stimulation with somatic depolarization (50 ms), filling a patch pipette with a Cs(+)-based solution, or extension of the duration of conjunction. We also found that intracellular infusion of a selective PKCα inhibitor (Gö6976) blocked LTD induction in the mutants, as in WT, suggesting that functional compensation occurred downstream of PKCα. The possibility that LTD in the mutants was caused by changes in membrane resistance, access resistance, or presynaptic property was excluded. The present results demonstrate that LTD is inducible by intensified conjunctive stimulations even in K882A and Δ7 mutants, indicating no contradiction against the LTD hypothesis of motor learning.


LTD; Marr–Albus–Ito hypothesis; cerebellum; motor-learning; slice

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