Signal processing in neurons

• Metabotropic neurotransmission

• Electrical signals in dendrites

• Active properties of dendrites

• Signal processing at the– Synapse (post)– Dendrite– Soma– Synapse (pre)

Neuronal Anatomy

• Dendrites– Input-spine

• Cell Body/Soma

• Axon– Output-bouton

Neural circuits, cartoon version

• Spindle afferents excite the homonymous motor neuron and inhibit antagonists

MNa

Agonist

Ia

Antagonist

MNb

IN

Excitatory synapse

Inhibitory synapse

Synaptic structure

Garner 2002

Modulation of Input E/I PSPs

• Synaptic strength (fast)– Efficiency of neurotransmitter release– Area/receptor number– Channel conductance/sensitivity

• Dendrite morphology (slow)– Input resistance– Membrane capacitance– Electrical propagation

NMDA receptor mediated plasticity• Glutamineric synapses have both AMPA and NMDA

receptors– Long term potentiation: Tetanus increases subsequent

EPSPs– Tetanic depolarization relieves Mg2+ block (NMDA)– Calcium induced channel phosphorylation increases

conductance– Long term potentiation

• Ca2+ influx via NMDA receptors

• DepolNMDACa2+CaMKIIAMPA

• Ca2+(PKA)-|I1->PP1-|AMPA

High frequency stimulationHigh CalciumI1 is inhibitedReduces PP1

Increases AMPA

Metabotropic neurotransmission

• GPCRs– Gs Adenyl Cyclase

• AC->PKA->channel phos (NaV)

– Gq phospholipase C• PLC->DAG->PKC->channel phos (AMPA)

– Gbg GirK G-coupled inward rectifying potassium channel

– Gbg CaV N, P, Q type voltage gated calcium channel

• Slow – seconds to minutes

Girk

• Hippocampal neurons

• GABAA channel

– 1300 pA Cl- current

• GABAB GPCR

– 50 pA K+ current– Slow kinetics– Different GABA

sensitivity

• Cooperative currentsdifferent time

Sodickson & Bean 1996

Picrotoxin blocks GABAA

Distinct I-V curvesDifferent reversal potentials

Ba2+ blocks K+

GABAA

GABAB

Metabotropic Neuromodulation

• DSI stimulation triggers fast and slow depolarization– Slow depolarization is GTP dependent– Blocked by non-exchangeable GDP--S

Stimulation

Recording

Slow metabotropic depolarization

Fast Ionotropic depolarization

Blocks metabotropic process

mGluR1 suppression of m-current

• M-Current: potassium current, near threshold, helps set excitability

• After-hyperpolarization

Young S R et al. J Neurophysiol 2008;99:1105-1118

DHPG is an mGluR agonistBrief exposure Long exposure Prolonged exposure to

DHPG results in sustained inactivation of m-current

Sustained, but not immediate suppression requires p38 MAP kinase

EPSPs recorded in CA3 neurons of guinnea pig

Dendrite Morphology

• Multiple synapses (10k+)

• Multiple morphologies

• Post-synaptic density

VI Popov et al., 2004 Neuroscience

Electrical interaction in dendrites

• Local depolarization propagates– Internal resistance– Membrane capacitance– Time constants RC

• Signal attenuation– Leak current

Extracellular

CmCmRm Rm

RiIntracellular

Active properties of dendrites

• NaV

– Low density prevents AP– PSP regeneration, amplification

• CaV

– T-type, low threshold– “Window current” bistatility– Additional calcium-mediated magic

• Ih

– Slow depolarization– Pacemaker

Multiple inputs

• Consider Unitary PSP 5 mV– Input current ~ 750pA = GV = G(0.060-(-0.060)– G=6250 pS (multiple channels at one synapse)

• Simultaneous PSP– G=12,100pS– Input current 1500 pA

• Second PSP during coincident wave:– G=6250; V=(0.06-(-0.055))= 115 mV– Input current = 720 pA

• Dendritic branches isolate circuits

Coincidence reinforcement

• “Hebbian” plasticity– Neurons that fire together, wire together– Reinforcement of synapse consequent to AP– Back-propagation of AP, faster than PSP

Stuart & Hauser, 2001

Current interactions

• Multiple ions, multiple gatings• Local to synapse or distributed• Experimental models are incomplete:

– Intact, decerebrate, isolated spine, slice, culture– Unique populations of neurons

• See Grillner (2003); construct potential in a CPG or motor neuron w/nifedipine, stychnine, etc

Axon hillock

• Integrates signals across dendritic tree

• Dense NaV, highest probability of AP

• Rheobase

• Chronaxie

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 20

1

2

3

4

5

Stim Duration (ms)

Stim

Am

pl (

nA)

ActionPotential

No ActionPotential

Rheobase

2x Rheobase

Chronaxie

Output Action Potential

• Presynaptic inhibition– Ionotropic

• Sub threshold depolarization of bouton• Reduce Ca2+ influx

– Metabotropic• mGluR group II & IIII• Local NT release feeds back on presynaptic

neruon

Sea slug (tritonia) locomotion

• Characteristic escape response

• Alternate, vigorous body flexion

• Simple neural circuit

Lawrence & Watson 2002

Tritonia CPG

• Escape is a programmed response– Katz, et al., 2004

Dorsal Swim Interneuron

Ventral Swim Interneuron

Ventral Flexion Neuron

Dorsal Flexion Neuron

Flex

ExtendIn

tracellular p

oten

tialo

f neu

ron

s

Stimulate sensory neurons to elicit escape

Tritonia Metabotropic Neuromodulation

• DSI stimulation triggers fast and slow depolarization– Slow depolarization is GTP dependent– Blocked by non-exchangeable GDP--S

Stimulation

Recording

Slow metabotropic depolarization

Fast Ionotropic depolarization

Blocks metabotropic process