Hello, my name is Jonathan Hanley.
I'm a senior lecturer in the
Department of Biochemistry
at the University of Bristol, and
my research focuses on neuronal cell
biology, in particular molecular
mechanisms that underlie changes
in synaptic strength, otherwise
known as synaptic plasticity,
which are thought to
underlie learning and memory
and are also proposed to
be involved in a number
of neurological diseases.
In this presentation, I will try
to give an overview of a number
of proteins whose major role
is to organize synapses,
or the so-called scaffold proteins.
As the name suggests,
a scaffold protein
provide structure to the
synapse and also acts
as a platform to bring numerous
specific protein components close
together to enhance signaling,
trafficking, or other cell
biological events that are crucial
for the function of the synapse.
I will start off by introducing
some basic concepts about synapses,
their plasticity, their
Since the title of this presentation
covers a very broad topic,
I will not be able to discuss
all aspects in great detail,
so I will focus on
and beyond that I will
focus mainly on three
multi-domain scaffold proteins
called GRIP, PSD-95, and SHANK.
I will describe their
normal synaptic function,
and finally, discuss their role
in some important neurological
disorders, or ASD, schizophrenia.
and brain ischemia.
The brain is the center
of the nervous system
and almost certainly the most
complex structure in biology.
All aspects of cognition
originate in the brain.
memories, ideas, and dreams.
The brain also provides
us with the ability
to see, hear, taste,
smell, touch, and move.
It allows us to form words,
understand mathematics, communicate
with others, make decisions,
compose, and appreciate art.
The human brain consists of more
than 100 billion neurons, which
process and transmits information
in the form of electrical signals.
Communication between neurons
occurs at specialized junctions
All of the normal faculties
I mentioned in the last slide
are the product of circuits made
up of multiple synaptic connections
that can be formed, strengthened,
weakened, or eliminated.
Synapses are the most fundamental
processing unit in the brain,
ad precise regulation of synaptic
development and connectivity
is critical for maintaining
accurate neuronal network
activity and normal brain function.
This regulation will depend largely
on the passing of stimulation
at that particular
synapse, in other words,
which receptors are
stimulated and which
signaling pathways are
In addition, a synapse would
also be subject to influence
from the rest of the neuron.
It is now widely believed
that information in the brain
can be stored in the form of altered
structure in chemistry of synapses
and or by the formation
of new synapses
and the elimination of
old ones in a process
broadly referred to as
Since the brain is the seat
of our cognitive processing,
it is not surprising that brain
dysfunction accounts for the most
and it is becoming increasingly
evident that dysfunction
at the level of the synapse is a
crucial aspect of many diseases.
This has led to the
to describe a disease
of the synapse.
in the brain express
both inhibitory and
Inhibitory synapses use the
neurotransmitters GABA or glycine,
with the corresponding
ionotropic receptors, GABAa
or glycine receptors.
Most excitatory synapses are
glutamatergic and express AMPAR
and NMDA receptors, and in
some cases, kainate receptors.
Inhibitory synapses are
found on the dendritic shaft
or on the soma, whereas
excitatory synapses are housed
in dendritic spines, which are tiny
protrusions on the dendritic shaft.
Both kinds of synapse have
extensive cytoskeletal components,
both actin and microtubules.
But the actin
cytoskeleton is thought
to be most important
in excitatory synapses.
Both kinds of synapse also express
a variety of transsynaptic adhesion
molecules that maintain
the synaptic connection,
but can also mediate bidirectional
signaling across the synapse
For example, neuroligins
post-synaptically and interact
with their presynaptic partners,
And of most relevance to this
talk, both kinds of synapse
have a high density of
specialized proteins associated
with the post-synaptic compartment
known as the post-synaptic density,
Many of these proteins are
so-called scaffold proteins
that underpin synaptic
function and plasticity.
You can get an impression
from this diagram
that the array of scaffolding
proteins at excitatory synapses
are more complex than
suggesting that excitatory synapses
are subject to more precise
regulation and are capable of a
higher level of signal processing.