2. Neuroscience Journal Club 19 February 2008 Henry Lester

3. Y Shu, A Hasenstaub, A Duque, Y Yu & D. A. McCormick (2006). Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential Nature 441: 761 and PNAS, 2007 H Alle and J R. P. Geiger (2006) Combined Analog and Action Potential Coding in Hippocampal Mossy Fibers Science 311: 1290 M. H. P. Kole, J. J. Letzkus, G. J. Stuart (2007) Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy Neuron, 2007 Hideki Kawai, Ronit Lazar & Raju Metherate (2007) Nicotinic control of axon excitability regulates thalamocortical transmission Nature Neurosci 10, 1168

4. Presynaptic voltage-dependent Ca channels are the major source of Ca influx leading to transmitter release. These Ca channels do not inactivate strongly on a ms time scale. On a ms time scale, the Ca sensors seem to integrate Ca influx. In nonsaturating regimes, release depends strongly on the Ca influx—probably to the 3 rd or 4 th power. Therefore transmitter release depends strongly on the duration of the presynaptic AP. Classical studies (Katz & Miledi, squid synapse) show...

5. The prevailing mode to encode information in the mammalian central nervous system is to convert an analog signal resulting from graded synaptic inputs into patterns of action potentials, which are transmitted as all-or-none signals along the axons. By contrast, in primary sensory systems and central neural circuits of small invertebrates, analog signals are used directly to transmit information. In many brain regions the axonal distances from the cell body to a large fraction of the corresponding presynaptic boutons are rather short and somatic subthreshold signals can be large in amplitude. The question arises whether analog axonal signaling contributes to information transmission in the mammalian brain. Paraphrased from Alle & Geiger, intro

7. O Belluzi, O Sacchi, E. Wanke (1985). A fast transient outward current in the rat sympathetic neurone studied under voltage-clamp conditions. J Physiol. 358:91-108 Caltech Neuroscience Journal Club, February 1986 Presented by Jeanne Nerbonne

8. Yu et al, Figure 1 The Basic Phenomenon: Depolarizing the Presynaptic Soma  Larger EPSP

9. Yu et al, Figure 3 The mechanism: Changes in somatic membrane potential affect amplitude & duration of somatic and axonal action potentials

10. Yu et al, Figure 4 Spontaneous barrages of synaptic activity propagate down the axon

11. EPreSPs: recorded in mossy fiber boutons; generated upstream of the CA3 region. Alle & Geiger Figs 1 & 2

12. Electrotonic propagation of somatic depolarizations underlies EPreSPs. Alle & Geiger Fig 3

13. Alle & Geiger Fig 3 Dual pre- & postsynaptic V-clamp: nerve terminal depolarizations do increase EPSCs

14. Kole et al, Fig. 1 One can patch onto 3-4 μm blebs in cut-off axons; this is useful

15. More bleb recordings

16. α-DTX specifically blocks Kv1.1*, 1.2*, or 1.6* channels; low doses of 4- AP block less specifically. Tityustoxin-Kα, which is relatively specific for K + channels containing Kv1.2 subunits strongly blocked the slowly inactivating K + current in cortical axons, whereas dendrotoxin-K, which is relatively specific for Kv1.1 subunits, exhibited only marginal effects.  Kv1.2* channels are the mediators of the D-current responsible for axonal spike repolarization. Immunocytochemical studies reveal the prominent expression of Kv 1.2 channels in axons and axonal terminal fields throughout the brain. In the neocortex, Kv1.2 is of particularly high density in the more distal portions of the axon initial segment of cortical pyramidal cells. Yu et al PNAS 2007 Kv1.2* channels appear to control AP waveform

17. More dual recordings

18. Kawai et al Nicotine enhances success rate for thalamocortical EPSCs...

19. ... because nicotine enhances success rate for thalamocortical axonal transmission Kawai et al Subcortical white matter Local nicotine perfusion STR =superior thalamic radiation axons

20. 200  m Medial Perforant Path Py Or Rad LMol Alveus Temperoammonic Path Chronic nicotine: increases perforant path  4* nicotinic receptor fluorescence ~ 2-fold TV Bliss, T L ö mo (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 232:331-56. Nashmi et al, 2007

21. 1 mV 10 ms 1 mV 10 ms Chronic Chronic Nicotine Chronic Acute Nicotine 10 min80 min 1mV 10 ms Saline Nicotine 0.5 mV Acute Nicotine Chronic 10 min 80 min Saline Nicotine 0.5 mV 5 ms Acute Saline Chronic Acute Saline Acute Simple model for cognitive sensitization: chronic nicotine + acute nicotine lowers the threshold for perforant pathway LTP Nashmi et al, 2007