Abstract
Calcium/calmodulin-dependent kinase IV (CaMKIV) phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB), which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP) in the anterior cingulate cortex (ACC) was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training) in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.
Highlights
The long-lasting changes of neural circuitry in forebrain structures including the anterior cingulate cortex (ACC) are believed to contribute to emotion, learning, memory and pain [1,2,3,4,5,6], and such long-term changes in neural circuitry may require new protein synthesis
We investigated if actinomycin-D, a transcription inhibitor, affects synaptic potentiation in ACC neurons induced by the paired training
calmodulin-dependent protein kinase IV (CaMKIV) is highly expressed in the ACC [19], little is known about how CaMKIV-induced protein synthesis contributes to the early-phase of synaptic potentiation in ACC neurons
Summary
The long-lasting changes of neural circuitry in forebrain structures including the anterior cingulate cortex (ACC) are believed to contribute to emotion, learning, memory and pain [1,2,3,4,5,6], and such long-term changes in neural circuitry may require new protein synthesis. Long-term potentiation (LTP) is typically divided into early-phase and late-phase LTP, in which the latter is mainly thought to be dependent on protein synthesis. At the CA1 [7] and CA3 [8] synapses, protein synthesis inhibitors disrupt late-phase but not early-phase LTP. Other studies reported that early-phase LTP in CA1 [9], CA3 [10], and dentate gyrus [11] was suppressed by protein. The CaMKIV-CREB pathway is required for protein synthesis-dependent late-phase LTP [17,18]. It is conceivable that CaMKIV is involved in early-phase LTP, because our previous study has shown that early-phase LTP in the ACC, amygdala, Brain region
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