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Outline. Cortex and hippocampus Space clamp error and dendritic patch recordings Dendritic spines and the postsynaptic density Ionotropic versus metabotropic neurotransmitter receptors Some general pharmacology Thermodynamics…. Cortex.

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Outline

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  1. Outline Cortex and hippocampus Space clamp error and dendritic patch recordings Dendritic spines and the postsynaptic density Ionotropic versus metabotropic neurotransmitter receptors Some general pharmacology Thermodynamics….

  2. Cortex Layer V pyramidal cells are huge cells that receive inputs both proximally (from layer II/III) and distally (from layer I). They project to the thalamus.

  3. The Trisynaptic Hippocampal Loop OUT IN

  4. Dendrites Magee, 1999 Johnston et al., 1996

  5. Space Constant () • = √(aRm)/(2Ri) • a = radius of cable If a= 500 nm, Rm = 100 MΩcm2 and Ri = 10 Ωcm, then = 50 µM • is the distance along an infinite cylinder over which a potential decays e-fold.

  6. Space Clamp Error

  7. Dendritic Spines Yuste and Denk, 1995

  8. The Postsyaptic Density

  9. Ionotropic Receptors Receptor and channel form a single structure. Kinetics of opening and closing are fast (ms timescale).

  10. Metabotropic Receptors Receptor is coupled to channels via a G-protein. Most neurotransmitters have both ionotropic and metabotropic receptors The timecourse is on the order of seconds

  11. Pharmacology Voltage Gated Channel Blockers: Na+- TTX (or from inside the cell: QX 314) K+ - TEA (or from inside the cell: Cs+) Ca2+ - Cadmium Ih (HCN) - ZD7288

  12. Pharmacology Ionotropic Receptor Antagonists: AMPARs - NBQX (also CNQX and DNQX) NMDARs - APV (also called AP5) GABAARs - Picrotoxin, bicuculline and gabazine Nicotinic AChRs - Curare, bungarotoxin GlycineRs - strychnine

  13. Pharmacology Metabotropic Receptor Antagonists: mGluRs GABABRs - CGP and saclofen Muscarinic AChRs - Atropine

  14. Equilibria Reactions k1 k2 A  B K (equilibrium constant) = [B]/[A] = k2/k1 this tells you where the equilibrium is going to lie Rate formation of B (V) = k1[A] Enzyme do not change the equilibrium of a reaction- they only reduce the energy of the transition state

  15. The Enzyme-Substrate Complex Observation by Michaelis: k3 k1 k2 E + S  ES  E + P Vmax = k3[Etotal]

  16. Michaelis-Menten Kinetics V= k3[ES] Rate of formation of [ES] = k1[E][S] Rate of breakdown of [ES] = (k2 + k3)[ES] The Michaelis Constant = Km = (k2 + k3)/k1 Michaelis-Menten equation: V = Vmax([S]/[S]+Km)

  17. Michaelis-Menten Kinetics V = Vmax([S]/[S]+Km) When [S] << Km, V is proportional to [S] When [S] >> Km, V is independent of [S] at Vmax When [S] = Km, V is Vmax/2

  18. Competitive vs Noncompetitive inhibition Competitive Noncompetitive By increasing [S], I can be overcome. Thus, Vmax remains the same. Km is shifted because I changes the apparent affinity of S for E. No amount of S can overcome I. Thus, Vmax is decreased while Km is unchanged

  19. Cooperativity There are two varieties of cooperativity that result in non-Michaelis-Menten (sigmoidal) plots “All or none”- you have multiple binding sites and all of them are required for the reaction to proceed “Facilitory”- you have multiple binding sites and the binding of one site facilitates the binding of the next site (changes the on/off rate constants)

  20. Cooperativity A Hill Plot is a log-log graph of the saturation of the enzyme versus the concentration of the substrate. The slope of the line is the “hill coefficient”- it is the degree of cooperativity. If the cooperativity is “all or none”, then hill coefficient is equal to the number of substrate molecules required for the reaction. If the cooperativity is “facilitory”, then the hill coefficient is a lower limit for the number of molecules.

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