Cell-Specific PKM Isoforms Contribute to the Maintenance of Different Forms of Persistent Long-Term Synaptic Plasticity.
Multiple kinase activations contribute to long-term synaptic plasticity, a cellular mechanism mediating long-term memory. The sensorimotor synapse ofAplysiaexpresses different forms of long-term facilitation (LTF)-nonassociative and associative LTF-that require the timely activation of kinases, including protein kinase C (PKC). It is not known which PKC isoforms in the sensory neuron or motor neuron L7 are required to sustain each form of LTF. We show that different PKMs, the constitutively active isoforms of PKCs generated by calpain cleavage, in the sensory neuron and L7 are required to maintain each form of LTF. Different PKMs or calpain isoforms were blocked by overexpressing specific dominant-negative constructs in either presynaptic or postsynaptic neurons. Blocking either PKM Apl I in L7, or PKM Apl II or PKM Apl III in the sensory neuron 2 d after 5-hydroxytryptamine (5-HT) treatment reversed persistent nonassociative LTF. In contrast, blocking either PKM Apl II or PKM Apl III in L7, or PKM Apl II in the sensory neuron 2 d after paired stimuli reversed persistent associative LTF. Blocking either classical calpain or atypical small optic lobe (SOL) calpain 2 d after 5-HT treatment or paired stimuli did not disrupt the maintenance of persistent LTF. Soon after 5-HT treatment or paired stimuli, however, blocking classical calpain inhibited the expression of persistent associative LTF, while blocking SOL calpain inhibited the expression of persistent nonassociative LTF. Our data suggest that different stimuli activate different calpains that generate specific sets of PKMs in each neuron whose constitutive activities sustain long-term synaptic plasticity.SIGNIFICANCE STATEMENTPersistent synaptic plasticity contributes to the maintenance of long-term memory. Although various kinases such as protein kinase C (PKC) contribute to the expression of long-term plasticity, little is known about how constitutive activation of specific kinase isoforms sustains long-term plasticity. This study provides evidence that the cell-specific activities of different PKM isoforms generated from PKCs by calpain-mediated cleavage maintain two forms of persistent synaptic plasticity, which are the cellular analogs of two forms of long-term memory. Moreover, we found that the activation of specific calpains depends on the features of the stimuli evoking the different forms of synaptic plasticity. Given the recent controversy over the role of PKMζ maintaining memory, these findings are significant in identifying roles of multiple PKMs in the retention of memory.
Department of Neuroscience, Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032, jh2004@cumc.columbia.edu.
Jiangyuan
0000-0002-4893-1862
J
Hu
Department of Neuroscience, Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032.
Kerry
0000-0003-0494-9312
K
Adler
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada, and.
Carole Abi
CA
Farah
Department of Psychology, McGill University, Montreal Neurological Institute, Montreal, Quebec H3A 1B1, Canada.
Margaret H
MH
Hastings
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada, and.|Department of Psychology, McGill University, Montreal Neurological Institute, Montreal, Quebec H3A 1B1, Canada.
Wayne S
0000-0003-1927-9315
WS
Sossin
Department of Neuroscience, Columbia University Medical Center, New York State Psychiatric Institute, New York, New York 10032.
Samuel
S
Schacher
D000818:Animals; D001048:Aplysia; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D057567:Memory, Long-Term / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000145:classification* / Q000502:physiology*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D013569:Synapses / Q000145:classification / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
D020033:Protein Isoforms; D011493:Protein Kinase C; D002154:Calpain
Aplysia; PKC; PKM; calpain; cell culture; long-term facilitation