The Background for our Research
Neurons communicate with each other through synapses. These highly specialized intercellular junctions are formed in a coordinated manner by both a presynaptic and a postsynaptic neuron. During development of the central nervous system (CNS), countless new synapses are established, and new synapses continue to form throughout life. At synaptogenesis, the surfaces of the pre- and postsynaptic neuron are in close proximity. Following this axo-dendritic contact, specialized membrane protein complexes are established at both of the juxtaposed neuronal plasma membranes. In this process, the membrane area destined to become the presynaptic plasma membrane forms the active zone, holding the synaptic vesicles that are ready for exocytosis, and the matching neurotransmitter receptors are recruited and retained at the postsynaptic membrane.
Recent progress
Recently, the first proteins have been identified that initiate the formation of synapses. One is SynCAM 1, a synaptic cell adhesion molecule that connects pre- and postsynaptic sides. SynCAM 1 is an immunoglobulin superfamily member with three extracellular Ig domains and a single transmembrane domain. This plasma membrane protein engages in a homophilic interaction, bridging across the distance of two cells, but it can also interact with neighboring SynCAM molecules in the same membrane. Importantly, SynCAM 1 alters neurotransmission and induces the formation of new, fully functional presynaptic terminals. This activity of SynCAM 1 allows the reconstitution of excitatory synaptic transmission in vitro (see Figure).
Our current goals
We aim to determine the molecular mechanisms of synapse formation in the developing CNS of vertebrates. Our goal is to identify and characterize the events that initiate synapse formation, and the steps that lead to its completion.
To achieve this goal, we pursue three aims. First, we examine the role of adhesion and signaling molecules in CNS synapse formation. These experiments involve biochemical characterization of SynCAM, and the functional analysis of its extracellular interactions in cultured hippocampal neurons. Second, we determine the intracellular SynCAM interactions driving synaptic membrane specializations. Here, we purify and characterize intracellular binding partners of SynCAM from brain. Third, we analyze the site of SynCAM action in pre- and postsynaptic membrane specialization. This set of studies is conducted in cultured neurons, and also in genetically altered mice to manipulate synapse formation in vivo and to test effects on synaptic plasticity and brain development.
Why we do it
Alterations in
synapse
formation affect synaptic plasticity, which is associated with
changes
in human behavior, learning and memory, and addiction.
Furthermore, deficits
of synapse formation and synaptic loss have been suggested for
neurodevelopmental
and neurodegenerative diseases. Determining the molecular
mechanisms of
synapse formation will allow to better understand to which extent
alterations
of these processes affect neuronal networks and are linked to
disorders
of the human brain. And from a molecular perspective, it is an
intriguing
challenge to unravel the rapid assembly of well organized pre-
and postsynaptic
membranes from a limited number of components in a locally
defined manner.
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Induction of presynaptic terminals and reconstitution of synaptic transmission. A. Illustration of the co-culture assay. A neuron (black) contacts a non-neuronal cell (green) that expresses SynCAM 1, a homophilic synaptic cell adhesion molecule. B. Model of the induction of presynaptic terminals in this assay. Extracellular interaction of neurons with SynCAM 1 triggers an unknown intracellular signal that leads to the formation of presynaptic terminals. These terminals can release neurotransmitter, which is detected by glutamate receptors (GluR2) expressed on the non-neuronal cell together with SynCAM 1.C. Image of a non-neuronal HEK 293 cell (silver, transmitted light image) in co-culture with hippocampal neurons (not shown), with presynaptic terminals on its surface (red, synaptophysin immunostaining).