Current events
Date: April 5th
Time: 09:30 am
Place : Gonda 2303
Title : "Prkcz null mice show normal learning and memory" and "PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory"
Speaker: David Glanzman
Authors: Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, McMahon T, Dadgar J, Fischbach-Weiss SC, Messing RO.
Abstract: Protein kinase M-ζ (PKM-ζ) is a constitutively active form of atypical protein kinase C that is exclusively expressed in the brain and implicated in the maintenance of long-term memory. Most studies that support a role for PKM-ζ in memory maintenance have used pharmacological PKM-ζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here we use a genetic approach and target exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-ζ (PKC-ζ) and PKM-ζ (Prkcz(-/-) mice). Prkcz(-/-) mice showed normal behaviour in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behaviour. Notably, Prkcz(-/-) mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz(-/-) mice. In vitro, ZIP and scrambled ZIP inhibited PKM-ζ, PKC-ι and PKC-ζ with similar inhibition constant (K(i)) values. Chelerythrine was a weak inhibitor of PKM-ζ (K(i) = 76 μM). Our findings show that absence of PKM-ζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-ζ is not present.
Authors: Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL.
Abstract: Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-ζ (PKM-ζ) has been reported to be necessary for both LTP maintenance and long-term memory. Inhibiting PKM-ζ activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-ζ pseudosubstrate sequence reverses established LTP in vitro and in vivo. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance, conditioned taste aversion, fear conditioning and spatial learning. However, most of the evidence supporting a role for PKM-ζ in LTP and memory relies heavily on pharmacological inhibition of PKM-ζ by ZIP. To further investigate the involvement of PKM-ζ in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-ζ and PKM-ζ. We find that both conventional and conditional PKC-ζ/PKM-ζ knockout mice show normal synaptic transmission and LTP at Schaffer collateral-CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKC-ζ/PKM-ζ knockout mice, indicating that the effects of ZIP are independent of PKM-ζ.
