1. BME 6938 Mathematical Principles in Neuroscience Instructor: Dr Sachin S. Talahthi

2. Excitable cells in the brain: Neurons

3. Anatomy of a typical neuron

4. More Detailed View of neuron anatomy

5. The neuronal cell membrane

6. Synapses

7. Excitability of neuron

8. Crash course on neuronal signaling  Neurons communicate through electrical signaling  Intracellular signaling is mediated through flow of ions through ion channels on cell membrane (Will discuss in details soon)  Long distance cell to cell signaling is mediated through generation of action potentials that propagate along the axons (focus of neuronal modeling will be to understand the dynamical mechanism’s underlying the generation of action potential)  Communication between neurons happen at synapses by the process of neurotransmission

9. Conduction of nerve impulse Unmyelinated axonMyelinated axon Animation of impulse propagation

10. Excitable properties of neuronal cell membrane: Intracellular signaling Essential fundamental laws in Cellular Neurophysiology:  Ficks Law of Diffusion  Ohms Law of Drift  Space Charge Neutrality

11. Fick’s Law of Diffusion Fick’s law relates the diffusion gradient of ions to their concentration.  J diff : Diffusion flux, measuring the amount of substance flowing across unit area per unit time ( )  D: Diffusion coefficient ( )  [C]: Concentration of the substance (ions) ( ) Ficks Law Animation

12. Ohms law of drift (Microscopic view) Charged particle in the presence of external electrical field E experience a force resulting in their drift along the E field gradient  J drift : Drift flux, measuring the amount of substance flowing across unit area per unit time ( )  : electrical mobility of charged particle( )  [C]: Concentration of the substance (ions) ( )  z: Valence of ion

13. Space charge neutrality Biological systems are overall electrically neutral; i.e., the total charge of cations in a given volume of biological material equals the total charge of anions in the same volume biological material

14. Some high-school chemistry  1 mole= Avogadro’s number (N A ) of basic units (atoms, molecules, ions…)  Concentration is typically given in units of molar.  1 Molar=1 mole/litre=10 -3 moles/cm 3  Relation between gas constant (R) and Boltzmann’s constant (k): R=kN A  Faraday constant F: Magnitude of one mole of charged particles: F=qN A

15. Some-algebra Membrane capacitance of a cell membrane is around 1 microF/cm 2. Concentration of ions within and outside of a cell is 0.5 M. Determine the fraction of free (uncompensated) ions required to charge a spherical cell of radius 25 micro m to produce 100mV? Ans: ~ 0.000235% For realistic cell dimension, from above calculations we see that generation of 10s of mV of voltage does not violate space-charge neutrality (~99.9% of charges are compensated)

16. Fundamental Equations of Cellular Neurophysiology  Nernst-Plank Equation  Goldman-Hodgkin-Katz Equation Are derived from the fundamental laws of neurophysiology that we talked about in lecture 2 ppt.

17. Nernst-Plank Equation: Reversal Potential  NPE describes the passive behavior of ion flow through biological cell membrane under the influence of concentration gradient and electric field  Reversal Potential: (Nernst Equilibrium potential) I=Current A/cm 2 ; u=molar mobility cm 2 /V-sec-mol; F=Faraday constant (96480 C/mol) R=Gas constant (1.98 cal/oK-mol); C=Concentration molecules/cm 3

18. Typical scale of reversal potential values Question: What is the direction of flow of following ions under normal conditions? 1.Na + 2. K + 3. Ca 2+ 4. Cl - (Hint: Look at the chart of reversal potentials and Nernst Equilibrium potential equation) At 37 o C mV

19. Specific Examples-Nernst Potential and the need for active mechanism  Ion concentration for cat motoneuron: V m =-70 mV  Nernst Potential: At body temperature 37 o C Inside mol/m 3 Outside mol/m 3 Na + 15150 K+K+ 5.5 Cl - 9125

20. Gradient maintenance  Active Transport:  Flow of ions against concentration gradient.  Requires some form of energy source  Examples: Na+ pump  Passive Transport:  Selective permeability to some ions results in concentration gradient  No energy source required  Passive distribution of ions can be determined using the Donnan rule of equilibrium

21. Graphical illustration of ionic current flow

22. Donnan Equilibrium Rule  The membrane potential equals the reversal potential of all ions that can passively permeate through the cell membrane.  Mathematically the Donnan Rule implies:  Have a look at Donnan Rule in works; through animaltion developed by Larry Keeley: http://entochem.tamu.edu/Gibbs-Donnan/index.html

23. Example: Application of Donnan Rule  Consider a two compartment system separated by a membrane that is permeable to K+ and Cl- but is not permeable to a large anion A-. The initial concentrations on either side of membrane are:  Is the system in electrochemical equilibrium (no ion flow across the membrane?  If not, what direction the ions flow? And what are the final equilibrium concentrations? Ion typeI (conc in mM)II (conc in mM) A-1000 K+150 Cl-50150

24. Goldman-Hodgkin-Katz Model  Relates the current carried by ion’s across the cell membrane to the transmembrane potential.  Can be derived as a solution to NPE equation under certain constraints:  The cell membrane is homogeneous medium (uniform thin glass)  Electric field across the cell membrane is constant  Ion’s flow independently without interaction  The flow of ion is affected by both concentration gradient and voltage difference across the membrane

25. Goldman-Hodgkin-Katz Current Eqn  Nonlinear I-V relationship for ionic current flow across a cell membrane under the influence of concentration and potential gradient (P=permeability of ion)

26. Goldman-Hodgkin-Katz Voltage Eqn  Commonly known as the Goldman equation; is used to determine the membrane resting potential of a cell that is permeable to several ionic species.  For membrane that is permeable to N positive ionic species and M negative ionic species:

27. Application of the GHK equation  Lets use GHK eqn to determine the contribution to membrane potential from active ion transport mechanism’s.  Na-pump result in flow of 3 Na+ ions across the cell membrane for every 2K+ ions. What is the resulting equilibrium potential of the cell of squid axon for which the concentration gradients across the cell are:  The permeability ratio is Pk:Pna=1:.03 Ion typeInside (mM)Outside (mM) K+40020 Na+50550