Neuroenergetics and the Kinetic Design of Excitatory Synapses

1. Neuroenergeticsand the Kinetic Design of Excitatory Synapses Paper by: David Attwell and Alasdair Gibb Nature Reviews Neuroscience Vol 6 (2005) DSI Artificial Cognitive Memory Journal Club 09 February 2011 Presented by: An Jingzhi

2. Content Overview of the Paper Analysis presented in the Paper - Energy Budget of the Brain - AMPA Receptor Affinity - NMDA Receptor Affinity - Glutamate Removal - Glutamate Receptor Signaling Bandwidth Conclusions and Perspectives Presented 1. Overview 2. Analysis Presented 3. Conclusions

3. The Big Picture “ … To investigate how the brain’s energy supply limits the maximum rate at which brain can compute, and how the molecular components of excitatory synapses have evolved properties that are matched to the information processing they perform ” Processing Power is Limited by ENERGY!! Brain’s Power to Process Info Consequences Metabolic Energy – ATP - Food Speed of Processing by Individual Neurons Multitude of Uses in Brain Ways to Deal with IT Limited Size Dendrite -Subthreshold Sypnatic Potential Axon – Action Potential Gain More 开源 Be Thrifty 节流 • Efficient Wiring • e.g. smaller neuron size, dist btw • Efficient Coding • e.g. sparse coding • Increase Blood Supply • Extract More Resources from the Supply (i.e. glucose and O2) • Evolve denser vascularisation 1. Overview 2. Analysis Presented 3. Conclusions

4. The Big Picture Proof of Limitation using Theoretical Energy Budget Chemical Kinetics Discussion of the Biological Design of A Excitatory Glutamate Synapse Processing Power is Limited by ENERGY!! • Synaptic Design Links Apparent Disparate Parameters • Apparently independent aspects of the brain’s design, such as energy supply, receptor kinetics and affinity, synaptic bouton anatomy and transporter properties are intimately related to each other • Mechanism of Information Retention and Extraction at Post-Synaptic Membrane • Proposed the collaborative role of various post-synaptic receptors in extracting the temporal components from the glutamate concentration increase caused by pre-synaptic action potentials 1. Overview 2. Analysis Presented 3. Conclusions

5. Energy Budget of Brain 1. Brain Typically Processes Information on Millisecond Scale Speed of Processing by Individual Neurons Dendrite - Subthreshold Sypnatic Potential Axon – Action Potential Mean in-vivo firing ≈ 4 Hz (250ms) Max in-vivo firing ≈ 100-300 Hz (3.33 – 10 ms) >> Speed of Information Processing is matched at dendrite – axon level Typical τm ≈ 1- 20ms Neuronal dendrite cut-off ≈ 200Hz (5ms) 1. Overview 2. Analysis Presented 3. Conclusions

6. Energy Budget of Brain 2. The Energy Supply to Brain is Limited… so speed of processing cannot be faster than ms scale Energy Budget of Brain 25 % Housekeeping 75 % Signaling Related More Flexible Manipulated by channel insertion… But increases energy demand to reset ionic balance! • Neurons are already designed to minimize Cm and it • Cannot keep decreasing • Need membrane • Increased sensitivity to noise 10% Maintenance of Resting Membrane Potential of Neuron 3% Maintenance of Resting Membrane Potential of Glial 87% Scales with the average Firing Rate x 1.15 = 100 % x 10 = 100 % Rate of ATP consumption is inversely proportional to Rm Power Action Potential Transmitter Recycling Pre and post synaptic flux 1. Overview 2. Analysis Presented 3. Conclusions

7. A Little Refresher… Synapses Chemical Electrical Inhibitory Excitatory Glutamate Acetylcholine Receptors Ionotropic Metabotropic mGluR NMDA Non-NMDA Secondary Messenger System kainate AMPA 1. Overview 2. Analysis Presented 3. Conclusions

8. AMPA Receptor Affinity Need to have kinetics that match up to the millisecond time scale, require fast glutamate unbinding and low glutamate affinity. Decay time constant of AMPA current = effect of glutamate unbinding + effect of kinetics of channel gating Amplitude weighted decay time constant = ~0.84ms >> Matched to information processing speed of brain 1. Overview 2. Analysis Presented 3. Conclusions

9. Glutamate Removal To prevent receptors from switching off by desensitization instead of deactivation; and the lost of information at synapses >> lower glutamate concentration in synapse on ms scale • Diffusion • One bouton releases glutamate • Need small synapse diameter • (<1um diffusion time is <1ms) • Glutamate Transporter • Large synapses • High frequency AP • Multiple bouton release >> glutamate transporter need to work on the time scale of 1ms High Transporter Density 200/um3 EAAT4 neuronal transporter 20800/um3 glial GLAST + GLT1 transporter 15200/um3 glial transporters Within 1ms of release, 4000 molecules of glutamate will encounter ~ 8000 – 12000 transporters Mechanism Overall cycle time of glutamate transporter is ~70ms; but initial removal step occurs at ~1 to 3ms; 1. Overview 2. Analysis Presented 3. Conclusions

10. NMDA Receptor Affinity Unbinding rate constant = 5 s-1; is 400x slower than AMPA Consequently, dissociation constant is also 400 times slower Amplitude weighted decay constant of 150ms >> much slower than ms scale, factor other than energy usage is important 1. Overview 2. Analysis Presented 3. Conclusions

11. NMDA Receptor Affinity >> COINCIDENCE MEDIATION (10s of ms) high-affinity receptor to temporally integrate information from low-affinity AMPA receptors 1. Overview 2. Analysis Presented 3. Conclusions

12. Glutamate Removal “ design of transporter is set by the need for transporters to have sufficient accumulative power to lower the extracellular glutamate concentration below the range that will tonically activate or desensitize glutamate receptors” >> stoichiometry of glutamate transporters is determined by the timescale over which NMDA receptors mediate coincidence detection 1. Overview 2. Analysis Presented 3. Conclusions

13. Signaling Bandwidth a-d) Response of glutamate receptors to increases in glutamate concentration of different durations. (akin to the arrival of high freq train of A.P.) Line:: response at the end of each step Circles:: peak response produced by each step >> occurrence and duration of a glutamate elevation can be encoded by AMPA receptor from ~ 0.1-10.0 ms >> NDMA has incomplete desensitization and is responsive up to ~ 300ms of glutamate elevation e) Includes also background study on kainate and glutamate; normalizing responses to body temperature using Q10=2.5; >> existence of several receptor types with different kinetics allow neurons to carry out different functions according to the duration of incident elevations in glutamate concentration. >> combination of AMPA, NMDA and mGluR receptors provides fairly efficient sampling of the entire duration range from 0.033ms to 20s 1. Overview 2. Analysis Presented 3. Conclusions

14. Summary Energy constraint limits speed of information processing in brain to millisecond scale AMPA receptors may have therefore evolved to function on the millisecond scale Consequently, glutamate removal from AMPA must work on a similar time scale NMDA receptors have kinetic properties catered to its role in synaptic plasticity Glutamate transporters have ionic stoichiometry set by the demand of NMDA; to avoid tonic activation of NMDA that might result in cell death Combined response of all glutamate receptors decomposes glutamate concentration increase triggered by the incoming action potential stream into different temporal components 1. Overview 2. Analysis Presented 3. Conclusions

15. Proposed Explanations Energy constraint limits speed of information processing in brain to millisecond scale:: why not faster mechanism? - limited capability to increase capillary density - limitation in energy supplied in food - co-evolution with musculoskeletal system NMDA receptors have kinetic properties catered to its role in synaptic plasticity:: why this particular time scale (<100 ms)? - minimize temporal jitter btw info converging from diff pathways Combined response of all glutamate receptors decomposes glutamate concentration increase triggered by the incoming action potential stream into different temporal components; why not finer division? 1. Overview 2. Analysis Presented 3. Conclusions

16. Future Work Investigate different information processing speeds for receptors at different brain region and how they relate to the local energy supply To perform a similar analysis on inhibitory synapses 1. Overview 2. Analysis Presented 3. Conclusions

17. Thank You. 1. Overview 2. Analysis Presented 3. Conclusions