CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP
How autophosphorylated CaMKII balances LTP and LTD at hippocampal synapses was unclear. Transgenic mice expressed a Thr286Asp CaMKII mutant with constitutive kinase activity. Mutants showed normal LTP at 100 Hz but a shift favoring LTD at 1-10 Hz.
Key findings
- Transgenic mice expressing constitutively active CaMKII (Thr-286-Asp mutation mimicking autophosphorylation) showed Ca2+-independent activity of 13–28% versus 7% in wild-type controls. Despite this elevated kinase activity, animals exhibited normal LTP in response to 100 Hz stimulation, demonstrating that excess Ca2+-independent CaMKII alone does not prevent high-frequency potentiation.
- At stimulation frequencies of 1–10 Hz, CaMKII-Asp-286 transgenic mice displayed a systematic shift in synaptic responses favoring LTD over LTP compared to wild-type. This frequency-response shift scaled with Ca2+-independent CaMKII activity, establishing the autophosphorylated kinase as a regulator of the bidirectional plasticity threshold in hippocampal CA1 synapses.
- The CaMKIIα promoter drove forebrain-restricted transgene expression at 10–21% of wild-type CaMKII mRNA levels across two independent lines (P3 and P15). Transcript was detected throughout dendritic layers of hippocampus, confirming proper subcellular targeting and providing a genetic model to dissect CaMKII autophosphorylation in bidirectional synaptic plasticity.
Abstract
To investigate the function of the autophosphorylated form of CaMKII in synaptic plasticity, we generated transgenic mice that express a kinase that is Ca2+ independent as a result of a point mutation of Thr-286 to aspartate, which mimics autophosphorylation. Mice expressing the mutant form of the kinase show an increased level of Ca(2+)-independent CaMKII activity similar to that seen following LTP. The mice nevertheless exhibit normal LTP in response to stimulation at 100 Hz. However, at lower frequencies, in the range of 1-10 Hz, there is a systematic shift in the size and direction of the resulting synaptic change in the transgenic animals that favors LTD. The regulation of this frequency-response function by Ca(2+)-independent CaMKII activity seems to account for two previously unexplained synaptic phenomena, the relative loss of LTD in adult animals compared with juveniles and the enhanced capability for depression of facilitated synapses.