Postsynaptic scaffold proteins in health and disease

Published on April 2, 2014   48 min
0:00
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.
0:49
I will start off by introducing some basic concepts about synapses, their plasticity, their molecular organization. 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 excitatory synapses, 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 diseases, Alzheimer's, autism spectrum disorders, or ASD, schizophrenia. and brain ischemia.
1:28
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. Thoughts, emotions, 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.
1:59
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 called synapses. 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.
2:26
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 consequently activated. 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 synaptic plasticity. Since the brain is the seat of our cognitive processing, it is not surprising that brain dysfunction accounts for the most neurological and psychiatric disorders, 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 term synaptopathy to describe a disease of the synapse.
3:34
Principal neurons in the brain express both inhibitory and excitatory synapses. 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 independently of neurotransmitter release. For example, neuroligins are expressed post-synaptically and interact with their presynaptic partners, the neurexins. 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, or PSD. 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 inhibitory synapses, suggesting that excitatory synapses are subject to more precise regulation and are capable of a higher level of signal processing.
Hide

Postsynaptic scaffold proteins in health and disease

Embed in course/own notes