Feedback and Feedforward Regulation of Interneuronal Communication

We formulate a mechanistic model capturing the dynamics of neurotransmitter release in a chemical synapse. The proposed modeling framework captures key aspects such as the random arrival of action potentials (AP) in the presynaptic (input) neuron, probabilistic docking and release of neurotransmitter-filled vesicles, and clearance of the released neurotransmitter from the synaptic cleft. Feedback regulation is implemented by having the released neurotransmitter impact the vesicle docking rate that occurs biologically through "autoreceptors" on the presynaptic membrane. Our analytical results show that these feedbacks can amplify or buffer fluctuations in neurotransmitter levels depending on the relative interplay of neurotransmitter clearance rate with the AP arrival rate and the vesicle replenishment rate, with faster clearance rates leading to noise amplification. We next consider a postsynaptic (output) neuron that fires an AP based on integrating upstream neurotransmitter activity. Investigating the postsynaptic AP firing times, we identify scenarios that lead to band-pass filtering, i.e., the output neuron frequency is maximized at intermediate input neuron frequencies. We extend these results to consider feedforward regulation where in addition to a direct excitatory synapse, the input neuron also impacts the output indirectly via an inhibitory interneuron, and we identify parameter regimes where feedforward neuronal networks result in band-pass filtering.