Neurons! John A. White Dept. of Bioengineering

Transcription

1 Neurons! John A. White Dept. of Bioengineering

2 What makes neurons different from cardiomyocytes? Morphological polarity Transport systems Shape and function of action potentials Neuronal firing patterns Different roles of Ca 2+ Methods of propagation Mechanisms of synaptic transmission Mechanisms of intracellular integration Glial support systems Synaptic plasticity Homeostatic plasticity

3 The father of modern neuroscience Morphological polarity Neuron doctrine: neurons are the basic structural and functional unit of the nervous system Ramon y Cajal Nobel prize

4 Morphological polarity Morphological polarity Law of dynamic polarization: nerve cells are polarized, receiving information on their cell bodies and dendrites, and conducting information to distant locations through axons Ramon y Cajal Berne and Levy

5 Morphological polarity Cajal s art Cerebral cortex Cerebellum Optic tectum

6 Transport systems Microtubule-based transport BE 6003 Salinas et al. (2008) Curr Opin Cell Bio 20: Fall 2010

7 Neuronal action potentials are Na + and K + dominated Shape and function of APs Berne and Levy

8 Shape and function of APs Refractory periods are short BE 6003 White (2000) Encyclopedia of the Human Brain Fall 2010

9 Shape and function of APs Crucial features of the neuronal action potential Na + channel inactivation Na + channel activation K + channel activation Na + channels are inactivated Impossible to generate another AP Na + channels still recovering from inactivation K + channels still recovering from activation Possible, but more difficult, to generate AP BE 6003 White (2000) Encyclopedia of the Human Brain Fall 2010

10 Neuronal firing patterns Neurons can fire at high rates BE 6003 White (2000) Encyclopedia of the Human Brain Fall 2010

11 Neuronal firing patterns Neurons can fire at high rates BE 6003 Colburn et al. (2003) J Assoc Res Otol 4: Fall 2010

12 Spike-rate adaptation is very common in neurons Neuronal firing patterns Dayan and Abbott, Fig. 5.6

13 Neuronal firing patterns SK-type Ca 2+ -activated K + channels often play a role in adaptation Calmodulin-binding domain Stocker (2004) Nature Reviews Neuroscience 5:

14 Cumulative inactivation of Na + channels is a 2 nd mechanism of adaptation Fernandez and White (2010) Journal of Neuroscience 5:

15 Cumulative Na + -channel inactivation is relieved by fluctuating inputs Fernandez and White (2010) Journal of Neuroscience 5:

16 Neuronal firing patterns Neuronal calcium channels L: Slow, largely noninactivating. Found in cell bodies, dendrites. P/Q, N: Slowly inactivating, presynaptic terminals R: More rapid inactivation than P/Q, N. Presynaptic terminals, proximal and distal dendrites. T: Low-threshold, rapidly inactivating. Soma and (distal?) dendrites. Khosravani and Zamponi (2006) Physiol Rev 86:

17 Multi-state activity in thalamocortical neurons Neuronal firing patterns BE 6003 McCormick and Pape (1990) J Physiol 431: Fall 2010

18 Different roles of Ca 2+ Major roles of Ca 2+ in neurons Triggers spike-rate adaptation Involved in bursting Triggers exocytosis at chemical synapses Involved in dendritic processing Local signal for synaptic plasticity Control signal for cellular homeostasis

19 Propagation in unmyelinated axons Methods of propagation BE 6003 White (2000) Encyclopedia of the Human Brain Fall 2010

20 Methods of propagation Myelination of axons BE Fall 2010

21 Methods of propagation Myelination of axons BE 6003 Berne and Levy Fall 2010

22 Methods of propagation Propagation in myelinated axons Refractory Spiking Charging Na + K + Na +

23 Myelinated axons have higher conduction velocities Methods of propagation BE Fall 2010

24 Mechanisms of synaptic transmission Electrical synapses BE 6003 Berne and Levy Fall 2010

25 Mechanisms of synaptic transmission Electrical synapses are resistive and bidirectional + G gap + V m(1) - C 1 G 1 V rest1 + - C 1 G 1 V rest2 + - V m(2) -

26 Mechanisms of synaptic transmission Chemical synapses BE 6003 Berne and Levy Fall 2010

27 Mechanisms of synaptic transmission Chemical synapses Immediately releasable pool: vesicles held close to plasma membrane by SNAREs Depolarization of presynaptic terminal Ca 2+ entry Fusion Diffusion of neurotransmitter across cleft Binding to postsynaptic receptor Recycling of neurotransmitter Ca 2+ BE 6003 Berne and Levy Fall 2010

28 Mechanisms of synaptic transmission Resupplying the immediately releasable pool Depol. of presyn. terminal Ca 2+ entry Activation of CaMKII Phosphorylation of synapsin I Synapsin I frees vesicles SNAPs and SNAREs dock the vesicle Ca 2+ BE 6003 Berne and Levy Fall 2010

29 Mechanisms of synaptic transmission Distinguishing features of Unidirectional Induce postsynaptic conductance change (usually an increase) chemical synapses inside + V m - outside C m G m V rest G syn E syn

30 Mechanisms of synaptic transmission Two distinct classes of chemical synaptic receptors Ionotropic Postsynaptic receptor is an ion channel Binding of ligand (neurotransmitter) changes P open Fast, transient, small gain Metabotropic Postsynaptic receptor is tied to postsynaptic 2 nd -messenger systems (usually G-protein-based) Slow, long-lasting, enormous gain

31 Mechanisms of synaptic transmission Major neurotransmitters and neuromodulators Amino acids Glutamate GABA (gamma aminobutyric acid) Glycine Acetylcholine Catecholamines Norepinephrine Dopamine Serotonin Peptides Opiods (endorphins, enkephalins, dynorphins) Substance P Gases Nitric oxide BE 6003 CO Fall 2010

32 Mechanisms of synaptic transmission Spontaneous release of single vesicles (quanta) BE 6003 Berne and Levy Fall 2010

33 Mechanisms of synaptic transmission Ionotropic EPSPs and IPSPs BE 6003 Berne and Levy Fall 2010

34 Mechanisms of synaptic transmission Quantal release Berne and Levy

35 Mechanisms of synaptic transmission Binomial model P(q = k) = N! k!(n k)! pk (1 p) n k E[q] = Np σ 2 = Np(1 p)

36 Mechanisms of intracellular integration Classical model of neuronal integration of inputs Excitatory inputs tend to innervate dendrites Inhibitory inputs tend to innervate cell bodies BE 6003 Berne and Levy Fall 2010

37 Mechanisms of intracellular integration Spatial and temporal summation BE 6003 Berne and Levy Fall 2010

38 Mechanisms of intracellular integration Cable theory λ 2 2 V m x 2 = τ m V m t +V m (x,t) V m 0 λ = a 2ρ i G m [=] mm τ M = C m /G m [=] ms

39 Mechanisms of intracellular integration DC response of infinite cable R = 1 2πa 3 / 2 ρ i 2G m

40 Mechanisms of intracellular integration Impulse response of diffusion equation Gaussian σ t

41 Mechanisms of intracellular integration Impulse response of infinite cable Gaussian σ t t /τ Area e

42 Mechanisms of intracellular integration Impulse response of infinite cable

43 Mechanisms of intracellular integration Assuming linear (passive) cable properties, neurons are very long Spruston (2008) Nature Rev Neurosci 9:

44 Mechanisms of intracellular integration Dendrites are highly nonlinear Häusser, Spruston, Stuart (2000) Science 290:

45 Mechanisms of intracellular integration Dendritic spikes may propagate only when coincident with more proximal inputs Spruston (2008) Nature Rev Neurosci 9:

46 Mechanisms of intracellular integration Back-propagating APs Golding et al.(2001) J Neurophysiol 86:

47 Mechanisms of intracellular integration K + channel density grows with distance from the soma BE 6003 Hoffman et al. (2001) J Neurophysiol 86: Fall 2010

48 Mechanisms of intracellular integration Modeling baps BE 6003 Acker and White (2007) J Comput Neurosci 23: Fall 2010