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 conditioned 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 training conditional and unconditional stimulus. 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 (mGluR7), which resides on the Purkinje cell synapses, 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 model tries to answer key aspects of the “Coding problem” of Neuroscience by focussing 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 — mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A and Protein Phosphatase 1 — which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different times. 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. Specifically, the time memory is encoded within the rate constants of the biochemical reactions and altering these rates constants means storing different time memory. The proposed mechanism is verified by a simplified mathematical model and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions. Author summary Hebbian plasticity is a widely accepted form of learning that can encode memories in our brain. Spike-timing dependent plasticity resulting in Long-term Potentiation or Depression of synapses has become a general consensus as a primary mechanism behind the formation of a substrate for memory formation within a neuronal population. However, recent experiments of conditional eyeblink response in Purkinje cells have challenged this point of view by showing that these mechanisms alone cannot account for temporal memory formation in the Purkinje cell. To explain the underlying mechanism behind this novel synaptic plasticity, we introduce a biochemical mechanism based on protein interactions occurring within a single synapse. These protein interactions and the associated rate constants are sufficient to encode time delays by auto-induced inhibition on a single excitatory synapse, suggesting that synapses are capable of storing more information than previously thought.