CaMKII at a central synapse : α-calcium/calmodium protien kinase II and synaptic plasticity at CA3 Schaffer collateral -- CA1 synapses in the mammalian hippocampus
Author(s)Hinds, Heather L., 1969-
Massachusetts Institute of Technology. Dept. of Brain and Cognitive Sciences.
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Long term potentiation (LTP) of synaptic transmission at the CA3-CA1 hippocampal synapse is a model synaptic plasticity mechanism that may underlie hippocampal dependent learning and memory. Inhibition of post-synaptic calcium/calmodulin protein kinase II (CaMKII) has been shown to block LTP, and a global knockout of the highly expressed a isoform of CaMKII caused an impairment in LTP and hippocampus dependent learning. We examined the role of CaMKII in CA3-CA1 LTP by selectively deleting [alpha]-CaMKII in adult hippocampal CA1 or CA3 pyramidal cells using conditional gene targeting. With this approach, we could investigate the locus of change that underlies LTP expression, as both pre- (CA3) and post- (CA1) synaptic CaMKII dependent mechanisms have been implicated, and further examine how CaMKII dependent plasticity contributes to learning and memory in a background of normal brain development. CA3-CA1 LTP is reduced in CA1 [alpha]-CaMKII knockout mice, suggesting that post-synaptic CaMKII is required for normal LTP. These mice are strikingly reminiscent of the a-CaMKII global knockout mice, demonstrating comparable LTP impairments and abnormal behaviors. In contrast, CA3 [alpha]-CaMKII knockout mice have normal LTP at CA3-CA1 synapses, suggesting that CaMKII phosphorylation of pre-synaptic synapsin I is not required for LTP expression. Contextual and cued fear conditioning were also normal in CA3 mutants, demonstrating that one form of hippocampus dependent learning is intact.(cont.) While several pre-synaptic short term plasticity mechanisms were unaffected in CA3 [alpha]-CaMKII knockout mice, repetitive stimulation protocols using short trains of stimuli of increasing frequency revealed enhanced frequency facilitation in mutants compared with controls. This suggests that CaMKII may be acting pre-synaptically as a negative regulator of neurotransmitter release during certain repetitive stimulation conditions, and as a "frequency detector" of calcium spikes, reaching higher levels of activation with increasing frequency of stimulation. Modulation of facilitation could be important to prevent synaptic terminals from depleting their vesicle stores during episodes of repetitive firing, or to maintain synaptic activity in an optimal range for information coding.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2001.Vita.Includes bibliographical references (leaves 153-180).
DepartmentMassachusetts Institute of Technology. Dept. of Brain and Cognitive Sciences.
Massachusetts Institute of Technology
Brain and Cognitive Sciences.