Neurons

Cells specialized for fast intracellular and intercellular

communication (information transfer)

Glial cells
Multiple functional roles
 Dendrites and soma: INPUT
Postsynaptic potentials in synaptic transmission

Axon initial segment: INTEGRATION *

CODIFICATION**
*Integrated postsynaptic potential
**Sequence (train) of action potentials

Assone: CONDUCTION
Action potential

Sinapsi: OUTPUT
Neurotransmitter release
Synaptic transmission
With increasing complexity of the nervous systems, there is an increase in the
number of neurons and their connections (from few units in the jellyfish to 1012
neurons and 1015 synapses in the human nervous system) as well as an
increase in the number of different neuronal types.

The different types of neurons differ in

--molecular properties (e.g. cf different set of V-gated ion channels resulting in

different firing properties).

--morphology of dendrites and axons (which contributes to determine the

neuron connectivity).

--connectivity, i.e. the number and types of different neurons to which a neuron
is synaptically connected (to which it transfers information) and the number
and types of different neurons from which it receives information via synaptic
inputs.

--synaptic properties (e.g. probability of transmitter release, synaptic plasticity)

depending on the identity of both the presynaptic and postsynaptic neuron.
 The morphology and the extension of the dendritic arborization contribute to
determine the number and types of synaptic inputs that the neuron receives.

cerebral cortex

Dendrite (in red)

Axon (in blue)

The length and branching of axons determine the number of synaptic contacts and the
types of connected neurons (cf presynaptic specializations along the entire axon).
Spine: dendritic protrusions (2 um; very narrow
neck) which contain the postsynaptic density
(PSD) specialization

Up to 30-40000 spines per pyramidal cell

 up to 30-40000 synaptic inputs
The form and complexity of the dendritic tree and the number of dendritic
spines are both very plastic:
they change on the basis of experience (cf synaptic plasticity, stress) and
during both development and ageing.
The nervous system is a network of diverse types of neurons (and glial cells)
communicating with each other mainly through synaptic connections.

Despite its key importance, the knowledge of neuronal connectivity (the

connectome) remains incomplete.

Neuronal conectivity can be described at multiple levels:

macro-scale:
long-range, region-to region conections inferred from imaging white-matter
fibre tracts in the living brain using DTI (diffusion tensor imaging).

meso-scale:
both long-range and local connections using various neuroanatomical tracers
(eg adeno-associated virus expressing EGFP) or brainbow

micro-scale:
at the level of individual synapses (e.g. through electron miscroscopy:
nanoscale)
 Brainbow: genetic strategy to generate lines of mice with stochastic combinatorial
expression in neurons (and glia) of multiple fluorescent proteins from a single
transgene, allowing the labeling of neurons with about 100 distinguishable colours.
- Useful for neuronal circuit analysis (e.g. number of neurons that innervate a
postsynaptic cell).

Purkinje Dentate gyrus in

neurons in hippocampus
cerebellum

C brainstem
CA1 hippocampus
D cerebral cortex
layers 3-5

Livet et al (2007) Nature

Cai et al (2013) Nature
Methods
 Mouse Brain Connectivity Atlas

--Injection of recombinant AAV expressing EGFP (under the synapsin-1 neuronal promoter) into specific
brain areas as an anterograde tracer to map axonal projections. To map axonal projections from specific
neuronal population can use Cre-driver mouse lines with a Cre-dependent AAV.
--EGFP-labelled axonal projections are imaged using serial two photon tomography (which combines
two-photon microscopy with automated vibratome sectioning of the entire mouse brain)

Oh et al, Nature 2014

Limitations:
postsynaptic neurons not labelled and therefore unknown (need to combine with retrograde tracing or
anterograde trans-synaptic tracing); microscale synaptic-level details are missing; insufficient to
understand function (for this, one needs functional connection strenght, i.e. synaptic physiology and
 Glial cells
Multiple functional roles
 Macroglia

Astrocites:
--10-50 % of the
volume of brain areas.

-- they are linked by

gap-junctions and
form a syncityum.
(A) A single astrocyte (B) An enlargement and
from the neocortex of surface rendering of the
an adult mouse; note astrocyte processes
the cell body, multiple shown in (A).
The large tick marks are 5 μm
branches, and in (A) and 0.5 μm in (B).
intricate fine highly
branched terminals.

R. Douglas Fields et al (2015) Neuron 86: 37-86

b) Computer 3D
reconstruction of a
mouse and human
cortcal astrocyte based
on glial fibrillary acid
protein immunostaining

d) Fluorescence image
of cortex section of
Brainbow mouse in
which 3 different
fluorophores were b) 3D reconstruction
expressed stocastically from electron
in astrocytes. microscopy data of four
Dark areas: neuronal dendrites (red, yellow,
cell bodies gold, purple) and
protrusions of nearby
Individual cortical astrocytic processes
(blue) in rat
astrocytes hippocampus.
occupy distinct
territories with
minimal overlap
Axel Nimmerjahn, Dwight E Bergles
Current Opinion in Neurobiology, Volume 32, 2015, 95–106
Many synapses are almost completely surrounded by
astrocytic processes (colored in red)
(da Van den Pol et al., 1994)
 Tripartite synapse
 Functional roles of astrocites:
1. Structural support for neurons

2. Support migration of neurons during

development

3. Clearance (removal) of ions (in particular

K+) from the extracellular medium (to avoid
neuronal depolarization)

4. Clearance (removal) of neurotransmitters

and ions (in particular K+) at the
synapses (to prevent spillover of neurotransmitter
and excitotoxicity)

5. Supply of metabolites and trophic factors

to neurons (and oligodendrocytes) (to
promote development and survival of brain cells and
promote formation of new synapses)

6. Contribute to create the blood-brain barrier

7. Contribute to intercellular communication

 Astrociti

(Blood capillary)
(endfeet)

Ramon y Cajal (1852-1934)

 Astrocytes contribute to create the blood-brain barrier
(that regulates the movement of molecules between the blood and the brain interstitial fluid:
It excludes toxic substances and protects neurons from circulating neurotransmitters, eg
glutamate, the blood level of which can increase strongly after eg a meal)

The small blood vessels of the brain are composed primarily of endothelial cells that continously line the
vessel luminal surface. Perivascular astrocytes extend processes that ensheathe most of the abluminal
microvessel surface.
The principal components of the blood-brain barrier are the endothelial cells and their extensive tight
intercellular junctions (in contrast with the large space between endothelial cells in general capillaries
allowing relatively non-selective diffusion). The blood-brain barrier is permeable in 3 ways: i) diffusion of
lipid-soluble substances; energy-dependent transport of specific water-soluble substances; ion channels.

Astrocyte foot processes are believed to influence barrier-specific endothelial differentiation

 Functional roles of astrocites:
1. Structural support for neurons

2. Support migration of neurons during

development

3. Clearance (removal) of ions (in particular

K+) from the extracellular medium (to avoid
neuronal depolarization)

4. Clearance (removal) of neurotransmitters

and ions (in particular K+) at the
synapses (to prevent spillover of neurotransmitter
and excitotoxicity)

5. Supply of metabolites and trophic factors

to neurons (and oligodendrocytes) (to
promote development and survival of brain cells and
promote formation of new synapses)

6. Contribute to create the blood-brain barrier

7. Contribute to intercellular communication

 Role of astrocytes in
intercellular communication

(da Van den Pol et al. 1994)

gliotransmitters
neurotransmitters glutamate
glutamate prostaglandins

ATP ATP
[Ca2+]
GABA NO
cytochines
Astrocytes Are Intimately Associated with Tens of Thousands of Synapses
through Highly Ramified Slender Branches
Astrocytes can influence neuronal connectivity by binding multiple synapses
and multiple neurons into functional assemblies, but astrocytes also operate at
a subcellular level to sense and modulate synaptic activity at single synapses.
 CNS PNS
Oligodendrocyte Schwann cell
Perineuronal
Oligodendrocyte of oligodendrocytes
white matter

Myelin
layers

axons

cell

Axon

The tight adhesion between the double

layers is mediated by protein-protein
interactions. The involved proteins have in
common highly charged intracellular
domains which neutralize the phospholipid
charges (besides extracellular domains
that favour adhesion).
Mutations in humans cause various
peripheric neuropathies
 Microglia

Macrofages of the central nervous system (defense system in response to

pathogens by phagocytosing them and by secreting pro-inflammatory cytochines)

Microglia cells are activated in pathological and inflammatory states.

They release cytochines and other molecules.

Other roles in physiological conditions e.g.

-survey of the microenvironment with their motile processes, that continously
contact neurons, axons and dendritic spines; the motility of processes changes in
response to extracellular signals including neurotransmitters and neuronal activity,
suggesting (still unclear) homeostatic functions;

-during development, synaptic pruning (elimination of synaptic structures)

dependent on neuronal activity and sensory experience (less active presynaptic
inputs are preferentially engulfed); also involved in engulfing neurons that die as a
result of programmed cell death

-regulators of activity-triggered synaptic plasticity, learning and memory (eg via

secretion of BDNF).
Salter and Stevens (2017) Nature Medicine