Neurons and Neurotransmission (Biological Aspects 1)

Biological Aspects of Brain Function (lecture 1: GC)

G Cocchini - course lecture slides

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Stain method

1875 - The stain method

Crucial moments:

During the second half of the 19th century (between 1870 and 1900) two scientists have provided a relevant contribution on the understanding of neurons:

Camillo Golgi (Stain method) and Santiago Ramon y Cajel

(Identification of axon and synapses) 

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Electrical transmission

In 1791 Luigi Galvani demonstrated that nerves conduct electricity

In a classical experiment, Galvani connected a nerve taken from a frog’s leg to a metallic wire. This was pointed to the sky during a thunderstorm (please notice that battery was invented about 10 years later by Volta) and it obtained muscular contraction of the frog’s leg. 

Nerve communication is electrical

ELECTRICAL SYNAPSES
Ions move from one neuron to another via direct physical connections between the neurons. 

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Chemical transmission

In a classical experiment Otto Loewi (1921) demonstrated that neurons communicate with each other by means of chemical transmission.

He placed two frog’s hearts in two different containers with a fluid.
He stimulated the vagus nerve (parasympathetic nerve) of one heart inducing the heartbeat to slow down.

He collected the fluid surrounding this heart and pouring it into the second container with the second unstimulated heart.

Then also the heartbeat of the second unstimulated heart start to slow down!

 

Nerve communication is electrical
Synapses communication is chemical ...and electrical!

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Chemical v Electrical synapses

Chemical and electrical synaptic transmission exist side by side, but they do so by very different mechanisms:

 Chemical synapses:

  • asymmteric morphology
  • unidirectional
  • slow (msec.)
  • synaptic cleft
  • divergence

Electrical synapses:

  • symmetric morphology
  • bidirectional (each cell pre- or post-synaptic)
  • fast (no delay)
  • no synaptic cleft but gap junction (pores) in membranes
  • synchronization role of large population of neurons (e.g. in retina
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Action potential

Action potential is sent from the cell body down the axon to the terminal buttons

There (synapse cleft) ,the neurotransmitter is released and it reaches the postsynaptic receptors.

This will result in an increase or decrease of the resting electrical activity of the postsynaptic membrane. 

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Neuron

A neuron consists of dendrites, a soma (body), axon and terminal buttons.

SOMA

Dendrites

They received “message” from presynaptic neuron and transfer it to the soma of the neuron

Axon

It is a relatively long tube that carries information (action potential) from the cell body to the terminal buttons. It can be covered by myelin (insulation cover).

 Terminal buttons

They secrete (release) the neurotransmitter into the synapse cleft

 

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Different types of neurons

Be able to recognise different types of neurons eg:

Unipolar neurons common in invertebrate or in the dorsal roots of vertebrate 

Bipolar neurons common in sensory systems

Multipolar neuron type is the most common in human nervous system. 

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Glia cells

Glial Cells (Glia)

These cells are much more common than neurons and they provide structural and chemical support to the neurons.

Types of glia:
-
Astrocytes hold neuron in place, nourishment to neurons and form the blood-brain barrier.
- Oligodendrocytes provide myelin, which is an insulating covering around the axon.

- Microglia contribute to clean up from dead

(Be able to recognise what each looks like) 

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Neural communication: Passive and active electrica

See diagram re Lipidic v Proteins

An ion is an atom with different number of protons (+) and electrons (-). This result in a positive or negative charged ion.

Ions distribution occurs according two general rules:

Electrostatic gradient: attraction/repulsion between different/similar charges

Osmotic balance or diffusion gradient: ions tend to spread around uniformly 

However, extracellular and intracellular environments are very different in terms of ion concentration.

This results in a different electrical charge. extracellular v intracellular

The inside is more negative than the outside. 

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Resting potential

Considering the outside as zero, the inside is 70mV

= RESTING POTENTIAL

The charge difference (resting potential) is due to a different concentration of sodium (Na+), potassium (K+), Chloride (Cl-) and organic anions (A-). 

This difference depends on two mechanisms:


a) sodium-potassium pump that forces out sodium ions (NA+) (Gated channels)
b) membrane permeability that allows ions to move more or less easier in and out side (Non-gated channels) 

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Depolarization

When an axon is stimulated with electric current, its membrane becomes more permeable to sodium (Na+) and potassium (K+)

then they move more freely across the membrane, i.e. mainly NA+ enters and K+ leaves the cell

the charge difference between intracellular and extracellular environment is reduced towards 0 mV. = DEPOLARIZATION 

The depolarization is restricted to the area stimulated.

Resting potential is quickly rest 

Depolarisation is mainly due to sodium (Na+) going inside,

Restoring of resting potential (repolarization) is mainly due 34 to potassium (K+) going outside 

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Action potential

When the stimulation is strong enough to produce a change over threshold we observe the
ACTION POTENTIAL
(rapid depolarisation and repolarisation of membrane)

ACTIVE and PASSIVE conduction:

Action potential= Active conduction 

The origin of the axon (axon hillock) is the region of the neuron where excitatory and inhibitory postsynaptic potentials take place.

If the sum of these overcomes a specific threshold, then the action potential is generated (“All-or-none law”).

When an action potential is generated this will be propagated along the axon. However, especially with long axon, it may takes a long time to reach the terminal buttons

SALTATORY CONDUCTION Some axon are partially covered by a fat substance called MYELIN

Action potential occurs at each Node of Ranvier

This speeds up the conduction of depolarisation 

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Frequency coding

  • A second action potential will fire only after the threshold has dropped back below the level of the sustained stimulus.

  • However in response of large depolarising stimuli second (an further) action potential will fired quickly

    the larger the stimulus, the higher the frequency of action potentials in the axon

page7image14112

stimulus intensity can be encoded by frequency code. 

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Synapse

Synapses can occur on soma, dentrites or other axons

At the proximity of the dendritic spines, the synaptic vesicles release the neurotransmitters into the gap between pre- and post-synaptic membrane (synaptic cleft) 

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Neurotransmitter 1

How is the neurotransmitter released by the vesicles?

The action potential opens calcium channels located in the presynaptic membrane.

These bind with the protein embedded in the membrane of the synaptic vesicles.

The fusion pores widen and membrane of vesicle fuses with pre- synaptic membrane (“Omega figure”) and the neurotransmitter is released into the synaptic cleft. 

After releasing the neurotransmitter into the synaptic cleft:

The open vesicle can then closes again and be refilled with neurotransmitter or merges the presynaptic membrane.

While the neurotrasmitter binds with postsynaptic receptors (like a “lock and a key”)

...and then it is quickly deactivated through two main mechanisms:

Re-activating pumps that send back the neurotransmitter into the presynaptic membrane (e.g. Acetylcholinesterase)

Broken-down or de-activation by enzymes
By diffusion of the neurotransmitter away from the region of synapse 

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Neurotransmitter 2

What is a neurotransmitter?

Today more than one hundred neurotransmitters have been recognised. The main relevant for nervous system are:

Noradrenaline (or Norepinephrine), dopamine, serotonin, GABA, acetylcoline and glutamate

Differences:
-Molecular structure, i.e. molecules vary in size and composition

Similarities:
- Synthesized by the presynaptic neuron
- Transported to the axon terminals to be stored in vesicles
- After binding with the postsynaptic membrane are removed or degraded. 

A complex modulation of information processing

Neurons can release one, two or several different neurotransmitters together or separately...
...and the type of neurotransmitter realised by a neuron depends on the rate of
stimulation.

Moreover, in some cases, the effect (i.e. increase or decrease firing) of a neurotransmitter on postsynaptic neuron depends on the postsynaptic neuron itself!

Conditional neurotransmitters. The neurotransmitter’s action is conditioned on the presence of another transmitter in the synaptic cleft 

However as a general rule:

Excitatory neurotransmitters are :

Acetylcholine (Ach), Catecolamine (i.e. Dopamine, Norepinephrine or Noradrenaline , Epinephrine), Glutamate, Histamine, Serotonine and other minor.

Inhibitory neurotransmitters are:

GABA, Glycine and other minor. 

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Postsynaptic membrane

What does happen in the postsynaptic membrane?

A postsynaptic cell is continuously in contact with thousands of neurotransmitters.

The biding between neurotransmitter and receptors results in a permeability change of the postsynaptic membrane. 

Some ions channels will be (directly or indirectly) open and ions will enter in the postsynaptic cell, resulting in a change in resting potential.

NMDA receptors are crucial in neuronal plasticity and memory pr

The SUMMATION of different effects will determine if the postsynaptic potential is excitatory or inhibitory

Finally, the postsynaptic potential will travel down to the axon hillock where, if the potential overcomes the threshold potential, an action potential will occurocess with calcium playing a fundamental role. 

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LTP v LTD

Long-term potentiation (LTP)long lasting increase in synaptic strength

Long-term depression = LTDlong lasting decrease in synaptic strength

Mechanisms inducing LTP (and LTD) can be different but glutamate and its receptors (in particular NMDA) are a crucial role.
and they can occur in different parts of the brain.

LTP has been mainly investigated in the mammal (e.g., rats) hippocampus. 

..what does it happens to membrane permeability?

If cell’s permability increases for positive ions then the resting potential will become more positive
excitatory potential

If the cell’s permeability
increases for negative ions then the resting potential will become more negative
inhibitory potential 

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Axons v Dendrites

Axon                                                 Dendrites

Resting potential -70 mV                  Resting potential -70 mV

All-or-none law (threshold)                Graded potential (no threshold)

Refractory period                              No refractory period  

Myelin can be present                       No myelin

Carry information from the soma       Carry information until the axon hillock

Active conduction (action potential)  Passive conduction

Grey and white matter                        Grey matter

Graded potential (no threshold)

Refractory period

No refractory period

Myelin can be present

No myelin

Carry information from the soma

Carry information until the axon hillock

Active conduction (action potential)

Passive conduction

Grey and white matter

Grey matter

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Neurotransmission

How do drugs affect neurotransmission?

They can interfere at different levels:

  1. 1)  Synthesisoftheneurotransmitter

  2. 2)  Itsstorageinvesicles

  3. 3)  Itsreleaseintothesynapse

  4. 4)  Reducingtheabilitytobindtoreceptorsites(antagonists)

  5. 5)  Preventing re-uptake of the neurotransmitter (agonist)

6) De-activation of the neurotransmitter by enzymes

Modification of neurotransmission:
To induce psychiatric disorders such as depression, psychosis; To treat psychiatric or neurological disorders.

Example: Amphetaminesincrease Dopamine schizophrenia

To know more about mental illness and neurotransmission see Wickens “Foundation of biopsychology” 2005. Chapter 10 

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Mirror neurons

In the 1980s and 1990s, Giacomo Rizzolatti, Leonardo Fogassi and Vittorio Gallese working at the university in Parma (Italy) run a number of experiments placing electrodes in the inferior frontal cortex of the macaque monkey to investigate neurons activity in action..... (see quote about mirror neurons)

  • Mirror neurons are a particular class of visuomotor neurons, originally discovered in the monkey premotor cortex (F5).

  • These neurons fire both when the monkey did a particular action and when it observed a similar action (Di Pellegrino et al. 1992, Gallese et al. 1996, Rizzolatti et al. 1996a).

  • Thus, the neuron "mirrors" the behavior of another animal 

Evidence of the existence of mirror neurons in human are only indirect (Neurophysiological and neuroimaging studies).

Altschuler et al. (1997, 2000) using EEG recordings
Hari et al. (1998) using magnetoencephalographic (MEG) technique. Individuals observe an action done by another individual, their motor cortex becomes active, in the absence of any overt motor activity.

Buccino et al. (2001) devised an fMRI study. Video clips showing transitive and intransitive actions compared to static similar pictures of hand/leg/mouth.

Mirror neurons in humans have been found in premotor cortex and parietal cortex of the brain 

 

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Checking my understanding (Neuron lecture)

  • What are electrostatic gradient and osmotic balance responsible for?

  • At resting potential the inside of the neuron is more........ Why?

  • A strong stimulus can increase ...... of action potential

  • Active and passive potentials: what’s the difference?

  • What is a graded potential? And where does it occur?

  • What does LTP mean? And what is it involved in? 

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