How Synapses Integrate Information and Change Rachel Stewart class of 2016 http://neuroscience.uth.tmc.edu/s1/chapter06.html http://neuroscience.uth.tmc.edu/s1/chapter07.html Chris Cohan, Ph.D. Dept. of Pathology/Anat Sci University at Buffalo 2016
OBJECTIVES 1. Understand how postsynaptic potentials differ from action potentials. 2. Understand how synapses integrate activity from multiple presynaptic inputs. 3. Understand the role of presynaptic Ca in short term changes in synaptic strength. 4. Understand how the NMDA receptor works 5. Understand the significance of LTP and how it depends on glutamate receptors.
NT Binding - Chemical to Electrical Signaling Postsynaptic potential created when Neurotransmitter binds to postsynaptic ionotropic receptor: excitatory - EPSP Vrest inhibitory - IPSP Vrest Properties: sign - determined by receptor graded in amplitude # vesicles released affects size Sum algebraically to allow integration of information electrical properties of postsynaptic membrane (V=IR) slower than APs why (more time for integration)
Synaptic Integration NS integrates info by algebraic summing of PSPs: temporal summation PSPs from 1 terminal close in time (eg E1 + E1) spatial summation PSPs from 2 terminals close in time (eg E1 + E2) Action potential frequency depends on sum of total synaptic activity. E1 resultant EPSP summation EPSP + IPSP summation
Position of Synaptic Terminals on Dendrite Synaptic terminals on dendrites farther from cell body have less effect on action potential initiation. Potentials get smaller with distance they travel along dendrite AP initiation zone -Summing point for PSPs
Reality The pattern of action potentials in neurons is determined from moment to moment by the probability of synaptic inputs how many are active + or location frequency of activity
Changes in Synaptic Function Short term changes in synaptic function are due to presynaptic Ca ++ modulation
Changes in presynaptic Ca modulate transmitter release: 1. Autoreceptor feedback Short Term Changes metabotropic receptors 2. Effect of other synapses Ca Ca influx Presynaptic inhibition # vesicles released Ca Ca Ca influx 3. Ca accumulates presynaptically when AP freq is high Presynaptic facilitation Ca # vesicles released Ca time
These integrative mechanisms allow synapses to change their effectiveness for short periods of time based on activity in the nervous system. Long term changes in synaptic effectiveness require other mechanisms.
Long Term Changes Ionotropic NMDA and AMPA glutamate receptors play essential roles in plasticity in the brain. They provide a mechanism for long term changes in synaptic function. They are also reasons for widespread neuronal death when the brain is injured.
Glutamate Receptors AMPA receptor Glu binding opens channel. Na + enters and depolarizes dendrite. produces epsp = excitatory synapse
Glutamate Receptors NMDA receptor Glu binding alone cannot open the channel because it is blocked by Mg ++ with an additional source of depolarization, Mg ++ is removed and Ca ++ and Na + flow into the cell. Ca ++ activates signaling pathways NMDA-R Ca + + Mg + + IMPLICATIONS 1. NMDAR opening requires an additional excitatory receptor/input 2. Ca ++ entry acts as a 2nd messenger to activate signaling pathways change synaptic strength. 3. Large amounts of Ca ++ enter cell if depolarization is prolonged.
Glutamate Receptors Glu + AMPA R = depolarization Glu + NMDA R = nothing! Glu + AMPA + NMDA: depolarization while Glu bound to NMDA R NMDA R now opens, causing Ca ++ influx
Glutamate Receptors Significance of Ca ++ influx through NMDA R: increase in strength of synaptic potentials lasting hours/months/years Long Term Potentiation (LTP) Mechanism: Ca ++ influx number of AMPAR large depol The increase in number of AMPA Rs causes a larger depolarization of postsynaptic cell. before time after Maintaining LTP for long periods of time requires protein synthesis and probably involves increases in number and size of synaptic contacts (spines).
LTD Long Term Depression Low level activation of a previously strengthened synapse leads to a sustained decrease in strength Long Term Depression (LTD) - loss of AMPA R before LTP LTD time
Glutamate Elevated glutamate is neurotoxic!! In stroke, brain injury, and degenerative diseases large amounts of glutamate may be released by injured nerve terminals. sustained depolarization sustained NMDAR open large Ca ++ influx glutamine astrocyte Nature Reviews Neuroscience
Glutamate Receptors Conclusion: LTP and LTD show how synapses can change their strength (connectivity) for long durations based on their history of activity. This is one mechanism neurons use to store and remove information about activity in the nervous system, which underlies important processes like learning, memory, and forgetting.
LTP and Learning Learning involves a prolonged change in synaptic efficacy that changes the function of neuronal circuits. Associative learning involves our ability recognize and remember the coincidence of 2 stimuli or events. LTP provides a cellular/molecular model for associative learning. Neuron 1 depolarizes dendrite. Neuron 2 has no effect on dendrite. Neuron 1 + 2 causes NMDA R opening and LTP with sustained increase in synaptic strength of neuron 2. Neuron 2 changed its effect due to simultaneous activation with neuron 1. 1 2 strong weak AMPA Rs NMDA Rs dendrite
Summary Synapses modulate electrical activity by both excitation and inhibition. They allow integration of activity based on the timing and distribution of inputs to a dendrite. Short term changes in synaptic strength result from changes in presynaptic Ca ++. Long term changes in synaptic strength require NMDA and AMPA receptors, which produce LTP. The resulting Ca ++ influx causes a larger depolarization and increased number of AMPA Rs at the synapse to ensure continued NMDA activation.