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Bi / CNS 150 Lecture 8 Synaptic inhibition; cable properties of neurons; electrical integration in cerebellum Wednesday, October 15, 2013 Henry Lester. Chapter 2 (p. 28-35); Chapter 10 (227-232). Nicotinic ACh, GABA A , and glycine receptors look alike at this resolution (prev. lecture).

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slide1

Bi / CNS 150 Lecture 8

Synaptic inhibition; cable properties of neurons;

electrical integration in cerebellum

Wednesday, October 15, 2013

Henry Lester

Chapter 2 (p. 28-35);

Chapter 10 (227-232)

slide2

Nicotinic ACh, GABAA , and glycine receptors look alike at this resolution (prev. lecture)

~ 2200

amino acids

in 5 chains

(“subunits”),

MW

~ 2.5 x 106

Binding

region

Membrane

region

Colored by

secondary

structure

Colored by

subunit

(chain)

Cytosolic

region

slide3

The pentameric GABAA and glycine receptors look like ACh receptors;

but they are permeable to anions (mostly Cl-, of course)

1. -amino-butyric acid (GABA) is the principal inhibitory transmitter in the brain.

2. Glycine is the dominant inhibitory transmitter in the spinal cord & hindbrain.

GABAA receptors are more variable than glycine receptors in subunit composition and therefore in kinetic behavior.

. . Cation channels become anion channels with only

one amino acid change per subunit, in this approximate location

Like a previous lecture

slide4

A Synapse “pushes” the Membrane Potential

Toward the Reversal Potential (Erev) for the synaptic Channels

ACh and glutamate receptors flux Na+ and K+,

(and in some cases Ca2+),

and Erev ~ 0 mV.

At GABAA and glycine receptors,

Erev is near ECl ~ -70 mV

Membrane potential

+80

+60

ENa

+40

At Erev , the current through open receptors is zero.

Positive to Erev, current flows outward

Negative to Erev, current flows inward

+20

-5

-20

Resting

potential

-50

-80

EK

-100

Like Figure 10-11

slide5

Pharmacology of GABAA Receptors: activators

  • Benzodiazepines (= BZ below):
    • Valium (diazepam), (Ambien, Lunesta are derivatives)

The natural ligand binds at subunit interfeces

(like ACh at ACh receptors)

phenobarbital site is unceratin

slide6

The AChBP interfacial “aromatic box” occupied by nicotine (prev. lecture)

. . . GABA and glycine also make cation-p interactions

aY198

C2

aW149

B

aY93

A

non-aW55

D

aY190

C1

(Muscle Nicotinic numbering)

slide7

GABAA and Glycine blockers bind either at the agonist site or in the channel

Strychnine

(glycine receptor)

Bicuculline

(GABAA receptor

Agonist

site

Picrotoxin

(GABAA & glycine

receptors)

slide8

How does the receptor transduce binding into channel gating? (prev. lecture)

CLOSED

OPEN

. . . Both ideas are also in play for GABA or glycine receptors

Swivel?

Miyazawa, Nature 2003

Twist?

Corringer, J Physiol 2010

slide9

We have Completed our Survey of Synaptic Receptors

Most

^

  • A. ACh, Serotonin 5-HT3, GABA, (invert. GluCl, dopamine, tyrosine) receptor-channels

Figure 10-7

slide10

direction of information flow

Postsynaptic

Presynaptic

neuron

neuron

little hill

(base)

(apex)

Parts of two generalized CNS neurons

Inhibitory

terminal

Excitatory

terminal

axon

presynaptic terminal

node of

Ranvier

initial

myelin

segment

axon hillock

cell

body

(soma)

apical

dendrites

basal

dendrites

presynaptic terminal

nucleus

postsynaptic dendrite

synaptic cleft

Like Figure 2-1

(rotated)

slide11

10% of the neurons

in the CNS are

cerebellar granule cells

The cerebellum: a famous circuit in neuroscience.

In today’s lecture,

it exemplifies pre- and postsynaptic structures.

Molecular

layer

Purkinje

cell layer

Ganule

cell layer

White

matter

Figure 42-4

slide12

A plurality of synapses in the CNS (> 1013 ) occur between

parallel fiber axons and Purkinje cell dendritic spines

Molecular layer

500 nm

slide13

Types of synapses

(Don’t mind the Type I, Type II stuff)

Figure 10-3

slide14

Types of synaptic integration

1. Temporal

A. Molecular lifetimes

B. Capacitive filtering

2. Spatial

3. Excitatory-inhibitory

slide15

Previous lecture

all molecules begin here at

t= 0

units: s-1

State 1

State 2

Synaptic integration 1A.

Molecular lifetimes

k21

open

closed

Concentration of acetylcholine at

NMJ

(because of acetylcholinesterase,

turnover time

~ 100 μs)

high

0

Number of open channels

ms

slide16

At the nerve-muscle synapse, acetylcholinesterase is present

at densities of > 1000 / μm2 near each synapse,

high enough to destroy each transmitter molecule

as it leaves a receptor

What causes the ~ δ-function of glutamate & GABA at CNS synapses?

Na+ -coupled transporters for glutamate & GABA

are present at densities of > 1000 / μm2 near each synapse,

probably high enough to sequester each transmitter molecule

as it leaves a receptor

(more in a few slides).

slide18

1B. Temporal Summation 2. Spatial summation

Recording Recording

Axon

Axon

Synaptic

Current

Synaptic

Potential

Long time constant

(100 ms)

Short time constant

(20 ms)

Synaptic

Current

Synaptic

Potential

Long length constant

(1 mm)

Short length constant

(0.33 mm)

~ 100 pA

Vm

2 mV

25 ms

Vm

Improved from Figure 10-14

slide19

1. If dendrites were passive, they would act like leaky cables . . .

Excitatory synapses

V

V

EPSP measured in dendrite

EPSP measured in soma

Gulledge & Stuart (2005) J. Neurobiol 64:75,

slide20

. . . and passively integrate inputs . . .

V

V

V

Δt = 0

Δt = 0

Δt = 5 ms

Prolonged

rising phase

Simultaneous,

colocalized

EPSPs

(two individual trials)

Nearly simultaneous,

colocalized

EPSPs

(two individual trials)

Simultaneous,

Spatially distinct

EPSPs

Inspect the simulation, and run the movie, at

http://www.neuron.yale.edu/neuron/static/about/stylmn.html

Gulledge & Stuart (2005) J. Neurobiol 64:75,

slide21

. . . but two-photon microscopes allow researchers to visualize patch-clamped dendrites in living animals . . .

Gulledge & Stuart (2005) J. Neurobiol 64:75,

slide22

25 μm

. . . dendrites are not passive. They have Na channels

Now break the patch,

to fill the cell with dye:

immunocytochemistry

* = axon hillock

Averaged traces

Whitaker, Brain Res, 2001

Magee & Johnston, J Physiol (1995)

slide23

brain slice

. . . voltage-gated Na+ and Ca2+ channels in dendrites

lead to

partial “backpropagation”

of

action potentials,

implying

that parts of cells

can process signals

semi-independently.

Stay tuned!

Gulledge & Stuart (2005) J. Neurobiol 64:75,

slide24

Excitatory-inhibitory integration:

  • The “veto principle” of inhibitory transmission

Inhibitory synapses work best when they are “near“ the excitatory event they will inhibit.

“Near” means < one cable length.

A. Inhibitory synapses on dendrites

do a good job of inhibiting EPSPs on nearby spines

B. Inhibitory synapses on cell bodies and initial segments

do a good job of inhibiting spikes

slide25

“Veto” inhibition at the axon initial segment:

Schematic of a GABAergic “chandelier cell” in human cerebral cortex

Inhibitory

Chandelier

Cell

Ch terminals

Ch.

axon

Pyramidal

Cells

Ch terminals

from Felipe et al, Brain (1999) 122, 1807

slide26

Now we localize the inhibitory “vetos”

of cerebellar Purkinje cells

by “pinceaux” (paintbrushes) of basket cells

Molecular

layer

Purkinje

cell layer

Ganule

cell layer

White

matter

Figure 42-4

slide27

How to localize and quantify inhibitory synapses

NH2

A fusion protein:

GABA transporter (GAT1)-GFP

slide29

<Immunocytochemistry

For GABA transporter

Molecular layer (basket cells stain)

Purkinje cell layer

“pinceux” (paintbrushes)

stain heavily

Granule cell layer

slide30

mGAT1 GFP

knock-in fluorescence >

<Immunocytochemistry

For GABA transporter

Molecular layer

(basket cells stain)

Purkinje cell layer

“pinceaux” stain heavily, showing

soma-hillock “veto”

Granule cell layer

slide31

GAT1-GFP expression in cerebellum:

basket cell terminals in molecular layer,

Showing dendritic “veto”

GABA transporter density is ~1000/(μm2)

50 mm

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