The role of the theta isoform of protein kinase C (PKC) in activity-dependent synapse elimination: evidence from the PKC theta knock-out mouse in vivo and in vitro.
PKC plays a critical role in competitive activity-dependent synapse modification at the neuromuscular synapse in vitro and in vivo. This action involves a reduction of the strength of inactive inputs to muscle cells that are activated by other inputs. A decrease of postsynaptic responsiveness and a loss of postsynaptic acetyl choline receptors account for the heterosynaptic loss in vitro. The loss is not seen in preparations in which PKC has been blocked pharmacologically. Here, we show that the loss does not occur in in vitro preparations made from animals genetically modified to lack the theta isoform of PKC. Synapse elimination in the newborn period in vivo is delayed but is eventually expressed in knock-out animals. PKC-dependent synapse reduction is suppressed in heterologous cultures combining normal nerve and PKC theta-deficient muscle, as might be expected from the postsynaptic locus of the changes that underlie the activity-dependent plasticity. Preparations in which PKC theta-deficient neurons innervated normal muscle also exhibited a marked deficit in PKC-deficient synapse reduction. The presynaptic action of PKC theta implied by this observation is blocked by TTX, and we propose that activity-related synapse strengthening is decreased by presynaptic PKC theta. Thus, PKC theta in both presynaptic and postsynaptic elements plays a critical role in activity-dependent synapse modulation and loss. We provide a model for activity-dependent synapse loss incorporating these findings.
Li
Min-Xu
MX
Section on Neurobiology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutesof Health, Bethesda, Maryland 20892, USA. liminxu@mail.nih.gov
Jia
Min
M
Yang
Li-Xia
LX
Jiang
Hao
H
Lanuza
Maria A
MA
Gonzalez
Carmen M
CM
Nelson
Phillip G
PG
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D015194:Diffusion Chambers, Culture; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008839:Microelectrodes; D009132:Muscles / Q000294:innervation / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D009435:Synaptic Transmission / Q000502:physiology*; D013997:Time Factors
D007527:Isoenzymes; D010703:Phorbol Esters; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta