A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

Within the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the conditional and unconditional training stimuli. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR(7)) was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed mechanism tries to answer key aspects of the Coding problem of Neuroscience by focusing on the Purkinje cell's ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins-mGluR(7), G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A, Protein Phosphatase 1 and other associated biomolecules-which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective dynamics of the biochemical reactions and altering these dynamics means storing a different time memory. The proposed mechanism is verified by both a minimal and a more comprehensive mathematical model of the conditional response behavior of the Purkinje cell and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.

Automated summary

Classical eye-blink conditioning experiments have shown that Purkinje cells in the cerebellum suppress their firing rates for a defined period of time in response to conditional stimuli after training. This suppression depends on the timing between conditional and unconditional training stimuli, with specific metabotropic glutamate receptors playing a key role. Proposed biochemical mechanisms suggest that time memory in individual Purkinje cells is encoded through the dynamics of proteins that self-organize into a complex, allowing for the encoding of different time durations. Validation of this mechanism has been supported by mathematical models and dynamical simulations, providing testable experimental predictions.