L3: Dendrites and dendritic integration

Dendrites and dendritic integration: Axon initial segment

• site at which AP is initiated

• between soma and first myelinated segment

• has a lower threshold for excitation→ certain types of VG channels

Dendrites and dendritic integration: AIS features

• has subtypes of voltage gated Na+ channels

  • some that are more sensitive to voltage

    • → require less depolarisation to open

  • some higher density of voltage gated Na+ channels

    • → contributing to a larger depolarisation in that region

Dendrites and dendritic integration: what determines whether the AIS is depolairsed sufficiently to inititate an AP?

Depends on the dendrites

Dendrites and dendritic integration: what do dendrites do

• receive signals from other neurons:

  • some neurons receive >10,000 synapses in their dendrites

    • EPSPs and IPSPs

• Propagate these to the AIS

Dendrites and dendritic integration: what is dendritic integration

• how the dendrites process and propagate these signals to the AIS

• How dendrite morphology and electrical properties influence the voltage at the AIS

Dendrites and dendritic integration: Features or dendrites

1. can be simple of complex

2. different lengths (distance from AIS)

3. different thicknesses→

   • Thicker when closer to soma

4. more or less branched

5. different numbers of spiney protuberances→ wwhere some synapses form (different distributions)

6. Even in a single neuron→ can be more than one dendritic tree

   • each having different properties

This can be in DIFFERENT neurons or even in the SAME neuron

More than one dendritic tree→ having different properties examples

1. basal and apical dendrites of cortical pyramidal neurons

2. density of spines can vary along the dendritic tree

signal processing can be different between the apical and basal dendrites

a→ the axon in the image on the right

Therefore dendritic integration is affected by

1. morphology of dendrites

2. (also) functional influences

Spines on dendrites, features

1. WHAT small compartments along dendrites

   • to increase SA for synapses

2. electrically isolated→ narrow neck

3. WHERE receive synaptic inputs:

   • Head→ excitatory

   • Neck→ inhibitory

4. Plastic

most dendrites have spines

Another way dendrites can differ from eachother

• distribution of spines

Dendritic potentials: dendritic signals are…

• postsynaptic potentials

Dendritic potentials: what are dendritic signals mediated by in the mammalian CNS

1. ionotropic glutamate receptors 

   • e.g AMPA receptors→ excitatory (EPSPs) 

2. ionotropic GABA receptors

   • → usually inhibitory (IPSPs)

   • this is due to their ionic permeability and the driving force on the permeant ions

Postsynaptic potentials are generated at…

• chemical synapses

• between presynaptic neuron and postsynaptic neuron

Excitatory and inhibitory synaptic inputs to spines, WHERE

1. Excitatory synapses form onto the

• heads of dendritic spines

• especially in the more distal dendrites

2. Inhibitory synapses form onto the

• Necks of spines

• WHERE: dendrites, soma, AIS → everywhere

• distal AND proximal

note: that previous years of imagingand species looked at are limited→ so distribution may actually be different

Relative number of inhibitory and excitatory synapses and location

• will vary in different neurons

→ comparing distribution of the exand inhib synaptic inputs

Excitatory synaptic inputs

1. presynpatic AP causes glutamte release

2. binds to AMPARs of the spine head

3. AMPAR ion channels→ permeable to Na+ ions

4. AMPAR-mediated Na+ current cuases EPSC

5. EPSC causes EPSP

6. But only a few mV

How does this propagate to AIS (even if so small?)

Length constant: what happens if an excitatory synpase is far out in the dendritic tree (distal dendrites)

1. EPSP must propagate along the dentries towards the soma

2. into axon to reach AIS

but…

Length constant: why is the passive propagation of a voltage signal along an axon or dendrite is not very effective?

1. Axons and dendrites are poor conductors of electricity

2. Due to high resistance to ionic movement within the cytoplasm and low resistance to ionic movement through ion channels in the membrane

i.e there is resistance:

• low→ Causes ions to leak out (Rm) 

• high→ stopping ions moving through the neuron (Ri)

Length constant: what does the length constant describe

• distance that a voltage signal will propagate bedore it decays to 37% of the initial value

For a large length constant we want

1. High Rm→ so stops ions leaking out

2. Low Ri→ so ions can move though axon quick

Length constant: if the resistance of the membrane is lower…

→ The length constant gets shorter 

Why?:

• More charged ions leak from the cytoplasm across the membrane

• or

• axon/dendrite diameter gets smaller (high resistance to current flow)
  

THEREFORE→ EPSPs will decay and be attenuated by the time they reach AIS

With an estimate of the denrite diamaer→ the length constant is

250 micro metres

How can a distal EPSP propagate ALL THE WAY to the AIS

However, because EPSPs are only a few mV in amplitude to start with

• by the time they are passivley propagated to the AIS

→ they may depolarise the membrane there by less than 1-2mV

this is not enough to gate the Na channels at the AIS

Example of human cell

• Purkinje cells

• length constant→ >400 microns

Then how does it travel so far???

→ → SUMMATION (passive linear integration)

Passive integration properties of dendrites: EPSPs and IPSPs are graded signals, meaning…

1. if more neurotransmiter is released

2. will bind to and open more ligand-gated ion channels

3. cause more ions to move across the membrane of the dendrite

4. generate larger voltage changes

Passive integration properties of dendrites: what is the signal limited by?

1. Number of vesicles of neurotransmitter releasted

2. number of LGICs present at a synapse

3. how long they can be open for before neurotransmitter is inactiavted or removed

Passive integration properties of dendrites

1. Temporal summation

2. Spatial Summation

 1 Passive integration properties of dendrites: what happens at excitatory synapses

1. single presynaptic action potential releases glutamate

2. causing: EPSP

1 Passive integration properties of dendrites: what happens when a second presynaptic AP, before the first has decayed…

1. second EPSP might be added on top of the first

ALTHOUGH: depends on the number of releasable vesicle in the presynaptic active zone

1 Passive integration properties of dendrites: Therefore, a train of APs can lead to…

• addition of EPSPs

• → SUMMATE TEMPORALLY to a larger amplitute

2. Passive integration properties of dendrites: spatial summation

1. typical CNS neuron have many different neuronal inuts

2. simulatenously activated

3. Spatial summation

2. Passive integration properties of dendrites: spatial summation why important?

• can give EPSPs enough power to bring the membrane at AIS

• → to threshold voltage

  • Required to initiate an action potential

Different receptors have different likelihoods of summation…

1. AMPA

vs

2. NMDA

Because the AMPA receptor-mediated currents are transient…

• a second synaptic stimulus will need to occur

• within few milliseconds of the first one

  • → in order to have an additive effect

however

• NMDA receptors first have to be relieved of a voltage-dependent block of the channel by Mg2+ ions

things are complex (even without considering inhibition)

Because NMDA receptors mediate longer-lasting currents…

• more likely to summate at lower frequencies of synaptic stimulation

But this summation of EPSPs must also work against…

• IPSPs

Where do IPSPs typically occur at in the mammalian CNS

1. GABAergic synapses

or

2. glycinergic synapses

Features of these synapses 

• have integral anion channels

  • → permeable to Cl-

• usually mediate IPSPs or inhibition

How do inhibitory synaptic inputs occur

1. presynaptic AP causes GABA release

2. GABA binds to GABA_ARs on the spine/neck/AIS

3. GABA_ARs ion channels are permeable to Cl- ions

4. GABA_ARs→ mediated Cl- current cuases an IPSC

5. The IPSC causes an IPSP

   1. or open Cl- channels cause ‘shunting inhibition’

What happens when the membrane permeability to Cl- increases?

1. Cl- ions will distribute themselves acorss the membrane

2. to maintain the Cl- equilibrium potential

why at rest or depolarised membrane potentials cause an inhibitory effect on membrane potential

• Beause the movement of Cl- will tend to be from

• outside→ into the cell

If E_Cl is near resting potential (as it often is), the effect of opening these channels…

1. increase the membrane permeability to Cl- ions

but

2. Without necessarily changing the membrane potential

→ ‘Shunting inhibition’

Why is this called shunting inhibition

• positive charge from the EPSP is effectively shunted 

  • (filtered or neutralised)

• through raised conductance of the membrane

• → WITHOUT hyperpolarisation occurring

Active integration properties of dendrites: how do axons overcome their limitations as electrical conductors?

• express voltage-gated ions channels

THEREFORE: they are active rather than passive conductors

Active integration properties of dendrites: are dendrites active or passive

• most dendrites can passively conduct electricity less than 1mm

• but there is some evidence to suggest dendrites are capable of active, non-linear transformations…

  • because they have VGICs

  • they do not show linear integration

e.g CNS dendrites can and do contain:

• voltage-gated ion channels

• including→ Na+, Ca2+ and K+ channels

• => leading to non-linear integration of inputs

Indications of this…

1. Dendrites of cerebellar Purkinje neurons→ report of active but poorly propagated signals in the

2. Mammalian CNS neurons→ direct measurements of voltage-gated ion channel currents→ see picture

How was this second experimental reslt obtained?

1. better patch clamp recording method

2. development of higher resolution calcium imaging method

blue→ soma

red→ dendrite

Example of this new technology

• simultaneous patch clamp recordings at the soma and in the dendrites of a pyramidal neuron showed:

  • Voltage-gated Na+ channels that resembled the action potential

  • seen in dendrite recordings

Example of this new technology: Because this occurred AFTER the AP at the soma

→ They are named ‘back-propagating action potentials (bAPs)’:

1. initiated at the AIS

2. then propagated simultaneously along the axon

3. back into the soma and dendrites

It is possible that these bAPS could contribute to…

• depolarisation of the postynaptic membrane

• at Excitatory synapses in spines

This enables…

1. relief of the magnesium block of the NMDARs

2. Facilitates NMDA receptor-dependent forms of synaptic plasticity

BUT could AP calso be initiated in the denrites?

• in various neurons a high density of voltage-gated Ca2+ channels or voltage-gated Na+ channels in distal dendrites appear to support dendritic action potentials/spikes

What does the initiation of Ca_v and Na_v- mediated action potentials in distal dendrites likely to assist with?

→ forward-propagation of dendritic potentials from synapse to AIS

Overall types of dendritic integration

1. Top→ PASSIVE INTEGRATION

2. left→ BACKPROPAGATION (from AIS initiation)

3. right→ ACTIVE INTEGRATION (AP initiated in dendrites)

Review questions 1

1. What is a likely source of current that causes depolarization in the dendrites and activates VGICs?

2. What is meant by a ‘back-propagated action potential’?

3. Which ions/ ion channels can mediate action potentials in dendrites?

Review Questions 2

1. What is meant by ‘dendritic integration’?

2. Which intrinsic properties of dendrites influence integration.

3. What is a ‘spine’

4. What conductance is usually active during an IPSP?

5. Explain what is meant by ‘temporal summation’ and ‘spatial summation’.

6. Explain what is meant by ‘shunting inhibition’.