Nonlinear Decoding and Asymmetric Representation of Neuronal Input Information by CaMKIIα and Calcineurin

How information encoded in glutamate release rates at individual synapses is converted into biochemical activation patterns of postsynaptic enzymes remains unexplored. To address this, we developed a dual fluorescence resonance energy transfer (FRET) imaging platform and recorded CaMKIIα and calcineurin activities in hippocampal neurons while varying glutamate uncaging frequencies. With little spine morphological change, 5 Hz spine glutamate uncaging strongly stimulated calcineurin, but not CaMKIIα. In contrast, 20 Hz spine glutamate uncaging, which induced spine growth, activated both CaMKIIα and calcineurin with distinct spatiotemporal kinetics. Higher temporal resolution recording in the soma revealed that CaMKIIα activity summed supralinearly and sensed both higher frequency and input number, thus acting as an input frequency/number decoder. In contrast, calcineurin activity summated sublinearly with increasing input number and showed little frequency dependence, thus functioning as an input number counter. These results provide evidence that CaMKIIα and calcineurin are fine-tuned to unique bandwidths and compute input variables in an asymmetric manner. [Display omitted] •CaMKII and calcineurin were corecorded via dual FRET in dendritic spines and soma•CaMKII and calcineurin respond distinctively toward input frequencies and numbers•CaMKII is a frequency/number decoder; calcineurin acts as an input number counter•Ca2+ amplitudes/integrals determine CaMKII/calcineurin activities, respectively An imaging platform has now been developed by Bito and colleagues and used to examine how the information contained in the frequency and number of glutamate releases is transformed into postsynaptic Ca2+ signaling. Their results uncover a nonlinear decoding mechanism by which Ca2+/CaM-dependent enzymes, such as CaMKIIα and calcineurin, can be activated in function of both input frequency and number in an asymmetric manner. Deciphering the enzymatic information processing at synapses provides a better understanding of the signaling machineries underlying synaptic plasticity.