1. Synaptic Homeostasis Sean Sweeney Module 725

2. mEPSPs are recordings of release of one vesicle/quantum. EPSP is a suprathreshold stimulation Of the nerve inducing the release Of multiple vesicles/quanta Quantal content is EPSP/mEPSP, a measure of the number of vesicles released per stimulus

3. ‘P’: The probability of the arrival of an action potential at the presynaptic compartment of a synapse inducing the induction of an action potential in the post-synaptic neuron or muscle How does a neuron set ‘P’

4. Plasticity: gain or reduction in synaptic efficiency P = a range between 0 and 1 P = the probability that the arrival of and action potential in the presynaptic cell will elicit an action potential in Plasticity correlates with experience, i.e, learning and memory processes

5. Neurons can change a number of parameter that would alter ‘P’ (during learning and memory for example) Also: concentration, sensitivity and composition of ion channels

6. mEPSPs are a measure of postsynaptic function i.e. a measure of the size of the postsynaptic receptor field mEPSP = 0.8mVmEPSP = 1mV

7. What keeps ‘P’ within a range? What prevents it from becoming ‘runaway’ How is ‘P’ set during Development? During Neuronal activity? How is ‘P’ regulated? (up and down) Activity sensors? Molecular mechanisms? The Neuronal Homeostatic Hypothesis.

8. The Homeostatic Hypothesis: Physiological parameters are maintained within a narrow range Does this apply in neurons? If the activity of a neuron is pushed beyond its normal operating range, adaptation occurs to change the gain of all synapses equally. Neurons can stabilise their excitability while retaining relative differences in strength among synapses. The return to a homeostatic set point would make sense in a system where a reproducible and reliable pattern of activity is required.

9. Evidence for Homeostasis: Alpha-bungarotoxin is a protein, binds tightly to an extracellular target and therefore slow to be cleared and localised in its effects: local injection of alpha-bungarotoxin can be used to ascertain long term effects of receptor blockage. Plomp, van Kempen and Molenaar (1992) J.Physiol. 458:487-499 Hemidiaphragms injected with alphaBTX every 48h for up to 6 weeks and compared to controls:

10. Plomp et al.,: After six weeks alphaBTX treatment: mEPPs were reduced in size by 57% of untreated control Quantal content was increased to 154%!! After a single injection of alphaBTX mEPPs were reduced in size by 60% but no increase in quantal content was observed! At timepoints between acute treatment and 6 weeks with alphaBTX quantal content increased, reaching a plateau Between 20 and 30 days. A mechanism of modulation?

11. Turrigiano et al., (1998) Nature 391: 892-896 Two day treatment of neocortical cells in culture with TTX or bicuculine (an activator of firing activity, KCL can be used alternatively) mEPSP and EPSP sizes are found to be Scaled!

12. Neurons have to work within a meaningful range of activity * * = epilepsy * * = complete silence

13. Homeostasis would act against plasticity?

14. Manipulations to test the homeostatic hypothesis: Davis and Goodman (1998) Nature 392: 82-86

15. In muscles that receive poor Innervation quantal size is increased

16. With increased innervation the probability of release is reduced

17. Homeostatic changes are observed due to differential levels of innervation

18. Manipulations in receptor content result in homeostatic compensation Petersen et al.,(1997)Neuron 19:1237-48 DiAntonio et al.,(1999) J.Neurosci. 19: 3023-32 Is homeostasis monitored by the receptors?

19. Paradis, Sweeney and Davis (2001) Neuron 30: 737-749 Manipulations of membrane excitability alter homeostatic responses

21. What happens in circuits when homeostatic changes are induced? Burrone, O’Byrne and Murthy (2002) Nature 420:414-418

22. Neurons expressing Kir2.1 receive fewer synaptic inputs from other cells when Kir2.1 is expressed prior to synaptogenesis

23. When the total cell culture is bathed in TTX, all synaptic parameters are equalised

24. Suppression of excitability After synapse formation Leads to a homeostatic Increase in synaptic inputs

26. Homeostatic responses include: Changes in mEPSP size Changes in mEPSP frequency Changes in synapse size The Homeostatic signal must be retrograde, i.e. post-synaptic compartment to presynaptic compartment What is the nature of the homeostatic signal?

27. Burrone and Murthy (2003) Curr Opin Neurobiol 13: 560-567 Davis and Bezprozvanny (2001) Ann. Rev. Physiol. 63: 847-869 Davis (2006) Annual Review of Neurosci. 29:307-23 Evidence from computer modeling.

28. Mechanisms and Molecules: Synaptic scaling mediated by Glial TNF-alpha (Stellwagen and Malenka, 2006, Nature 440; 1054-1059 Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA Receptors Shepherd et al., 2006 Neuron 52; 475-484

29. Glia Glia are involved in reuptake of neurotransmitter and may monitor neuronal activity: At the synapse At the network level Glia (possibly) monitor glutamate and in response secrete TNF-alpha. TNF-alpha induces the removal of AMPA receptors from the post-synaptic membrane Stellwagen and Malenka

30. Arc/Arg3.1 is an ‘immediate early’ gene Arc/Arg3.1 mRNA traffics to dendrites and accumulates in response to activity At the dendrite, Arc/Arg3.1 mRNA is translated (ribosomes present at synapse!) Arc/Arg3.1 protein interacts with dynamin and endophilin to induce endocytosis of AMPA receptors from the post-synaptic membrane, reducing receptor activation

31. Questions: How is the homeostatic ‘set point’ set? How is the homeostatic ‘set point’ monitored?