Synaptic transmission Mostly focus on presynaptic models Some postsynaptic receptors: have been shown in class John Jacques

Communication between neurons Background Communication between neurons

Communication between neurons Background Communication between neurons Staggering diversity of synapse morphologies and types in the brain Fundamental process of synaptic transmission same A key quantity in neural circuits is the synaptic efficacy or strength, which varies over time. long-term potentiation and depression constitute the basis of learning and memory

Synaptic Transmission Principles Arrival of an action potential Release of neurotransmitter Binds to receptors Generate a response in the postsynaptic neuron

Synaptic vesicle cycle Docked vesicles lie close to plasma membrane (within 30 nm) Primed vesicles fuse with the plasma membrane by sustained depolarization high K+, elevated Ca++, hypertonic sucrose treatment Fusion release transmitter near calcium channels The ‘active zone’ Exocytosis Endocytosis Reserve pool (80-95%) Recycling pool (5-20%) Readily-releasable pool (0.1-2%; 5-10 synapses per active zone)

EPSP and IPSP Excitatory Neurotransmitters: ACh and glutamate Inhibitory Neurotransmitters: Glycine and GABA

Postsynaptic effects

Transmitter release T(t): amount of transmitter released into the synaptic cleft at time t. N(t) available for release vesicles changes over time since the occupancy of the pool changes during neural activity p(t)release probability dramatically increases upon the arrival of a presynaptic AP Focus on the action of ionotropic receptors ion channel that opens when transmitter is bound

Postsynaptic conductance proportional to the amount of transmitter released Equation 2 above peak conductance is denoted by gm

Outline Short term plasticity Vesicle depletion and facilitation discuss biological background and plausibility Mechanistic aspects of these models Vesicle depletion and facilitation Use-dependent vesicle replenishment Receptor desensitization Stochasticity of synapses Outlook/Conclusion

Short term plasticity Synaptic depression and facilitation Depression: progressive reduction of the postsynaptic response during repetitive presynaptic activity Facilitation: an increase synaptic efficacy. Different mechanisms with different time constants Not mutually exclusive most synapses express some combination of these two mechanisms Variable between different neuron types

Short term plasticity: PSD STP: Factors located in the presynaptic terminal contain vesicles filled with neurotransmitter Opposed by the postsynaptic density (PSD) Area that contains a large number of different proteins implicated in synapse maintenance and plasticity contains the bulk of the neurotransmitter receptors mediating the postsynaptic response

Short term plasticity: PSD Opening of voltage gated calcium channels (VGCC) Intracellular concentration increase increases the probability of vesicle fusion with the cell membrane subsequent release of transmitter into the synaptic cleft (equation 1) activity-dependent; function of time. [Ca2+]i and release probability p not linear The release of a single vesicle smallest signal transmitted to the postsynaptic neuron spontaneous current small fraction in terminal in AZ

Vesicle depletion model : depletion Presynaptic vesicles are a limited resource during ongoing activity can lead to a suppression of the postsynaptic response model predicts an exponential decay of the postsynaptic response (A) Time constant order of seconds Faster decay- higher p steady state values decrease more slowly with increasing frequency (E) Suggests other mechanism

Vesicle depletion model : facilitation Depression model counteracted by facilitation accumulation of residual calcium in the synaptic terminal causes rapid VGCC facilitation increases the release probability after each presynaptic spike Time constant : range of tens of milliseconds much faster than vesicle replenishment

Use-dependent vesicle replenishment accelerate after intensive stimulation. increase in intracellular calcium concentration Enhanced vesicle replenishment included in the depletion model adding some form of activity-dependent component to Equation (7) Use-dependent replenishment reflect faster recruitment due to more efficient endocytosis A main function of mechanism maintain the ability of a synapse to transmit during sustained periods of high activity

RECEPTOR DESENSITIZATION THE OTHER SIDE: RECEPTOR DESENSITIZATION Synaptic depression due to desensitization the state of the population of receptors D(t) (10) Recovery from desensitization order of tens of milliseconds only effective during intense episodes of activity desensitization important property of receptors contribute to synaptic depression during physiological activity levels

Stochasticity of synapses Transmitter release postsynaptic current fluctuates from time to time. Changes in the synaptic parameters due to short term plasticity cause changes in the average postsynaptic response magnitude of the fluctuations measured by the coefficient of variation: (11)

Outlook/Conclusion Theoretical models have contributed much to our understanding of synaptic transmission and short term plasticity Relationship between depletion and facilitation key variables in these models have direct measurable correlates Not straight forward to experimentally interfere with short term plasticity   Valuable tool that enables analysis beyond the experimentally feasible. Short term plasticity may related to homeostatic effects or metabolic efficacy of synapses

Hennig, Matthias H. “Theoretical Models of Synaptic Short Term Plasticity.” Frontiers in Computational Neuroscience 7 (2013): 45. PMC. Web. 3 Oct. 2017. Destexhe, A., Mainen, Z. and Sejnowski, T. (1994). Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism. Journal of Computational Neuroscience, [online] 1(3), pp.195-230. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8792231 [Accessed 2 Oct. 2017]. REFENCES

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