PKC activation during training restores mushroom spine synapses and memory in the aged rat

Protein kinase C (PKC) epsilon and alpha activation has been implicated in synaptogenesis. We used aged rats to test whether the PKC epsilon/alpha activator blyostatin and PKC epsilon-specific activator DCP-LA combined with spatial memory training could restore mushroom dendritic spinogenesis and synaptogenesis. Compared with young rats, aged, learning-impaired rats had lower memory retention; lower densities of mushroom spines and synapses in the apical dendrites of CA1 pyramidal neurons; fewer PKC epsilon-containing presynaptic axonal boutons; and lower activation and expression of two PKC epsilon/alpha substrates, the mRNA-stabilizing protein HuD and brain-derived neurotrophic factor (BDNF). PKC activator treatment combined with spatial memory training restored mushroom spines and mushroom spine synapses; rescued PKC epsilon/alpha expression and PKC/HuD/BDNF signaling; and normalized memory to the levels seen in young rats. These effects were produced by treatment with either bryostatin or the PKC epsilon-specific activator, DCP-LA. Bryostatin also reversed alterations in GABAergic inhibitory postsynaptic currents (IPSPs) in aged, learning-impaired rats. Thus, our results support the therapeutic potential of PKC activators when added to cognitive rehabilitation for inducing mushroom spine synaptogenesis and reversing memory decline associated with aging. (c) 2013 Elsevier Inc. All rights reserved.