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Summary Molecular and Cellular Neurobiology NWI-BMD001D
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Summary Molecular and Cellular Neurobiology NWI-BM001DLecture 1 - Ultrastructure of the mammalian synapse/Molecular mechanisms of
neuronal communication
Learning outcome:
o Name or indicate specific structures on images of synapses: In the exam you can get an image
of an synapse this can be an EM image or an schematic figure and the question could be: Can
you indicate where this or that structure is? or the structure could be already indicated and you
have to explain what the structures is.
Active zone, PSD, synaptic vesicles, spinal microtubuli, spinal neck, calcium channels, NT,
NT transporters
o Know how synapses can be classified based on the type of neurotransmitter, postsynaptic
receptors, postsynaptic responses and their ultrastructural morphological features
Inhibitory: Glycine, GABA
Excitatory: Glutamate
Neuromodulatory synapses: Serotonin, Dopamine
Type 1: asymmetric synapse: excitatory – depolarization - cations
Type 2: symmetric: inhibitory -hyperpolarization - anions
Synapse: is a specialized cell-cell junction that allows neurons to communicate with each other and
non-neuronal target cells (e.g. muscle cells, glands, or blood vessels).
One can discriminate two types of synapses:
Þ Chemical: neurotransmitter-based to communicate
Þ Electrical: electrically coupled
Neuronal circuit: multiple neurons linked together by a set of synapses in series
A typical neuron in a mammalian brain contains > 10,000 synapses. In an adult human brain this is
estimated to contain >1014 synapses (100 trillion). Due to this large amount of synapses the brain is able
to perceive and function as it does.
There is diversity in the synapses in the brain. One can distinguish different types of synapses based on
the neurotransmitter that is used. Some examples of neurotransmitters are:
Þ Glutamate, GABA, glycine, dopamine, acetylcholine, (nor)epinephrine, serotonin
With these mentioned neurotransmitters also co-transmission can occur in a single synapse:
For example GABA, which is an inhibitory neurotransmitter, is often found with glycine as a co-
transmitter
Synapses can also be distinguished on the post-synaptic response that they induce:
Þ Excitatory (e.g. glutamate): post-synaptic depolarization. Pre-synaptic neuron will excrete
glutamate it will bind to its receptor which is located at the post-synaptic neuron which is
actually an ion-channel that is gated by the neurotransmitter. The channel opens and influx of
positively charged ions leading to depolarization.
Þ Inhibitory (e.g. GABA and glycine): post-synaptic hyperpolarization. Through binding,
negatively charged ions causes hyperpolarization. It will reduce the likelihood of generating
an action potential what would then involve the activation of the post-synaptic cell.
, Þ Neuromodulatory (e.g. dopamine, serotonin): no ionotropic receptors, induce biochemical
changes in post-synaptic neuron. G-protein coupled receptors.
Another way to distinguish the synapses is by the anatomical location of the synapses: central (between
neurons in the central nervous system) versus peripheral synapse (outside central nervous system) (e.g.
neuro-muscular junction, neuro-endocrine junction, autonomous neuro-effector junctions).
Chemical synapse
On the left you can see a schematic overview of the
synaptic vesicle cycle. With the pre and post-synaptic
neurons. The post-synaptic cell expresses receptors
which are in clusters at the PSD
(PostSynapticDensity). Those receptors will bind the
neurotransmitters that are secreted by the presynaptic
neuron resulting in activation of the channels and
therefore the post synaptic response.
The presynaptic cells contain the neurotransmitters
and concentrates itself in synaptic vesicles. The
neurotransmitters are pumped into the vesicles by
neurotransmitter transporters. These transporters also
have two types and thus differ in function. The
transporters in the membrane assure the re-uptake of
the released neurotransmitters in the vesicles. The
transporters in the synaptic vesicle membrane assure
the neurotransmitter uptake into the vesicles.
Once the vesicles are formed, there will start a series of steps on the active zone:
Þ Docking of the vesicle
Þ Priming of the vesicle
Þ Fusion of the vesicle with the pre-synaptic membrane this only happens when the neuron is
activated which results in the influx of calcium through the voltage gated calcium channel.
Because of the fusion the presynaptic membrane will enlarge in size. However, not long after
this endocytosis of the membrane will occur. Therefore, recycling the synaptic vesicles. The
vesicles are then acidified by a proton pump of H+. This is essential to allow later the uptake of
the neurotransmitter into the synaptic vesicle.
Ultrastructure of the mammalian synapse
Central synapse: Where the axon of a presynaptic neuron contacts the dendrite of a postsynaptic neuron
it can also be the cell body or the axon that it contacts.
Type I = asymmetric synapse: excitatory; mainly on dendrites and dendritic spines
Type II = symmetric synapse: no dendritic spine; inhibitory; concentrate on cell soma and axonal
initial segment
Active zone (AZ): Specialized region on the presynaptic plasma membrane, where synaptic vesicles
are docked and primed for release; the AZ is aligned with the postsynaptic density (PSD)
Molecular composition of PSD: neurotransmitter receptors, trans synaptic adhesion molecules,
scaffolding molecules, signal transduction molecules.
,1: synaptic vesicles
2: mitochondria 2
3: Active zone 1
4: PSD 5 3
5: Synaptic cleft 4
7
6: Spine neck 8
7: Spine apparatus 6
8: Dendritic microtubules
9: stalk of axon
B: asymmetric synapse
F2: symmetric synapse
3D reconstructions of axons and dendritic spines
Green: dendrite
Red: synapse
White: axon
Blue: mitochondria
MSB: multisynaptic boutons
(more than one postsynaptic partner)
SSB: single synaptic boutons
NSB: Nonsynaptic boutons
(no postsynaptic partner)
MVB: multivesicular body
Mito: mitochondrion
Sp: spine
F: filopodia like protrusion
St: stubby protrusion
M: mushroom shaped spine
T: thin shaped spine
Red surfaces: PSD areas
White: dendrite
Example question
1. Which of the following are neuromodulatory neurotransmitters:
a. GABA - inhibitory
b. Glutamate -excitatory
c. Dopamine – neuromodulatory like serotonin
d. Glycine – inhibitory
Lecture 2 – Synaptic cell adhesion molecules (SCAMs)
Learning outcomes:
o Deduce the different functions of cell adhesion molecules
Apposition of the post and pre synaptic neurons, mediate trans synaptic recognition and
signalling processes essential for the establishment of synaptic plasticity
o Describe the different stages of synapse formation and function, and the role of SCAMs in each
of these stages: Establishment, Assembly, Specification, Plasticity
o Give examples of SCAMs and their functional domains neurexin and neuroligin, functional
domains are LNS, Cadherin, leucine rich repeats, immunoglobulin
o Schematically draw SCAMs to illustrate how they function Neuroligin binds to 6th LNS of a-
neurexin or the LNS of b-neurexin
, Synaptic cell adhesion molecules SCAMs: are
transmembrane proteins (or at least proteins that are linked to
the membrane) which are localized at the synapse (either
presynaptic or postsynaptic, or both) and interact with each
other across the synapse (trans synaptic)
Þ Synaptic junctions are organized by trans-synaptic
cell adhesion molecules bridging the synaptic cleft
Þ SCAMs do not only connect pre- and postsynaptic
compartments, but also mediate trans-synaptic
recognition and signalling processes that are essential
for the establishment, specification and plasticity of
synapses.
Synaptic plasticity: the capacity of synapses to adjust their properties in response to previous activity
Examples of SCAMs:
Þ a/b-Neurexins (presynaptic)
Þ Neuroligins (postsynaptic) Implicated in schizophrenia and autism
Þ Ig-domain proteins e.g. synCAMs
Þ Receptor phosphotyrosine kinases (phosphorylate other porteins) and phosphatases
(dephosphorylate other proteins).
Þ Leucine rich repeat protein
Four stages of synapse formation and function
1. Establishment – pre- and postsynaptic partners will
approximate each other. They will interrogate each other
whether they will fit together molecularly by SCAMs.
Shortly, it involves recognition of pre- and postsynaptic
neurons: this process may require heterophilic and
homophilic interactions between SCAMs to recognize
appropriate synaptic partners.
2. Assembly – the synapses are assembled. Recruitment of
synaptic vesicles to the AZ and PSDs; during this stage
intracellular parts of SCAMs regulate physical cell-cell
adhesion and serve as anchor proteins to cluster or recruit
receptors or components of the pre- and postsynaptic
signalling machinery.
3. Specification – functional specification stage: SCAMs are
responsible for the organization of the molecular
components of the synapse, resulting in functionality of the
synapse. Similar to stage 2.
4. Plasticity – Synaptic plasticity: SCAMs may contribute to
structural and functional synaptic plasticity in activity
dependent adaptive events. They can for instance recruit
more synaptic vesicles to the AZ meaning more
neurotransmitters to be released. Or recruit more post
synaptic receptors resulting in a higher chance for activation
of the post-synaptic cells.
Note: synapses continue to be formed and eliminated during the lifetime of an organism.
Functional domains of SCAMs
The adhesive function of SCAMs is based on a limited number of extracellular domains, often
assembled into repeat units:
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