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Synaptic transmission • Presynaptic release of neurotransmitter • Quantal analysis • Postsynaptic receptors • Single channel transmission • Models of AMPA and NMDA receptors • Analysis of two state models • Realistic models Synaptic transmission: CNS synapse PNS synapse Neuromuscular junction Much of what we know comes from the more accessible large synapses of the neuromuscular junction. This synapse never shows failures. Different sizes and shapes I. Presynaptic release II. Postsynaptic, channel openings. I. Presynaptic release: The Quantal Hypothesis I. Presynaptic release A single spontaneous release event – mini. Mini amplitudes, recorded postsynaptically are variable. Assumption: minis result from a release of a single ‘quanta’. The variability can come from recording noise or from variability in quantal size. Quanta = vesicle A single mini Induced release is multi-quantal Statistics of the quantal hypothesis: •N available vesicles •Pr- prob. Of release Binomial statistics: P( K | N ) ( Pr ) (1 Pr ) K N K N K Binomial statistics: Examples N P( K | N ) ( Pr ) (1 Pr ) K K K •N available vesicles •Pr- prob. Of release mean: K Pr N variance: N Pr (1 Pr ) 2 Note – in real data, the variance is larger Example of cortical quantal release Yoshimura Y, Kimura F, Tsumoto T, 1999 Short term synaptic dynamics: depression facilitation Synaptic depression: • Nr- vesicles available for release. • Pr- probability of release. • Upon a release event NrPr of the vesicles are moved to another pool, not immediately available (Nu). • Used vesicles are recycled back to available pool, with a time constant τu dN r Pr N r (t ti ) N u / u dt N u N r NT Nr Nu 1/τu Therefore: dN r Pr N r (t ti ) ( NT N r ) / u dt And for many AP’s: dN r Pr N r (t ti ) ( NT N r ) / u i dt Show examples of short term depression. How might facilitation work? II. Postsynaptic, channel openings. There are two major types of excitatory glutamate receptors in the CNS: •AMPA receptors And • NMDA receptors Openings, look like: but actually Openings, look like: How do we model this? Nr [Glu] [Glu] dN s s (Glu ) ( N r N s ) s N s dt How do we model this? A simple option: dPs s (Glu ) (1 Ps ) s Ps dt Assume for simplicity that: s (Glu) k [Glu ] s constent Furthermore, that glutamate is briefly at a high value Gmax and then goes back to zero. dPs s (Glu ) (1 Ps ) s Ps dt Assume for simplicity that: s (Glu) k [Glu ] s constent Examine two extreme cases: 1) Rising phase, kGmax>>βs: dPs k [Glu ] (1 Ps ) dt Ps (t ) (k [Glu ] Ps (0))(1 exp( t k [Glu])) Ps (0) Rising phase, time constant= 1/(k[Glu]) Ps (t ) (kGmax Ps (0))(1 exp( t k[Glu])) Ps (0) τrise Where the time constant, τrise = 1/(k[Glu]) 2) Falling phase, [Glu]=0: dPs s Ps dt Ps (t ) Ps (max) exp( s t ) rising phase combined Simple algebraic form of synaptic conductance: Ps Pmax B(exp( t / 1 ) exp( t / 2 )) Where B is a normalization constant, and τ1 > τ2 is the fall time. Or the even simpler ‘alpha’ function: Ps Pmax t s which peaks at t= τs exp( t / s ) Variability of synaptic conductance through N receptors (do on board) A more realistic model of an AMPA receptor Closed Bound 1 K1[Glu] K-1 Open Bound 2 K2[Glu] K3 K-2 K-3 Kd K-d Desensitized 1 Markov model as in Lester and Jahr, (1992), Franks et. al. (2003). NMDA receptors are also voltage dependent: Jahr and Stevens; 90 [ Mg ] GNMDA 1 exp( V / 16.13) 3.57mM 2 1 Can this also be done with a dynamical equation? Why is the use this algebraic form justified? NMDA model is both ligand and voltage dependent Homework 4. a.Implement a 2 state, stochastic, receptor [Glu] Assume α=1, β=0.1, and glue is 1 between times 1 and 2. Run this stochastic model many times from time 0 to 30, show the average probability of being in an open state (proportional to current). b. Implement using an ODE a model to calculate the average current, compare to a. and to analytical curve c. Implement using an ODE the following 5-state receptor: Closed Bound 1 K1[Glu] K2[Glu] K-1 K-2 Bound 2 K3 Open K-3 Kd K-d Desensitized 1 K1=13; K2=13; K3=2.7; Kd=0.9 [mM/msec]; [mM/msec]; [1/msec]; [1/msec]; K-1=5.9*(10^(-3)); [1/ms] K-2=86; [1/msec] K-3=0.2; [ 1/msec] K-d=0.9 Assume there are two pulses of [Glu]= ?, for a duration of 0.2 ms each, 10 ms apart. Show the resulting currents Summary