Once synaptic partners have correctly targeted each other, both sides of the synapses must transform to form a functioning synapse (a process called synaptic differentiation). We are interested in identifying and characterizing trans-synaptic cues that direct synaptic differentiation in the mammalian central nervous system.
Interestingly, retinal synapses in the dLGN appear morphologically distinct from retinal synapses in all other regions of the brain. In fact, it appears that single retinal axons that branch to innervate multiple brain regions will form morphologically and functionally unique synapses in dLGN compared with other retino-recipient regions. For example, in dLGN at least 2 flavors of retinogeniculate synapses exist – those with a single retinal input (termed simple retinogeniculate synapses) and those which contain retinal inputs that originate from many (as many as 14!) different retinal axons (termed complex retinogeniculate synapses). We are now exploring molecules that are necessary for distinct steps in terminal development in dLGN. We found that FGF22, a molecule we previously identified as being critical for nerve terminal assembly at the neuromuscular junction, is important for the initial formation of retinal terminals in mouse dLGN (Singh et al. 2012). Now we are investigating what transforms these immature synapses into simple and complex retinogeniculate synapses. Several intriguing candidates have been identified and are under current investigation. We are particularly interested in what drives the assembly of complex retinogeniculate synapses as such studies may provide tools to begin to investigate the functional significance of this newly appreciated high level of retinal convergence onto thalamic relay cells.
Left: Serial Block Face Scanning Electron Microscopy 3D reconstructions of a single retinal axon (red) that synapse onto both dendrite and soma of a relay cell (yellow) in adult mouse dLGN, forming a complex RG synapse.
Right: Serial Block Face Scanning Electron Microscopy 3D reconstructions of a several retinal axon synapsing onto shared region of a relay cell dendrite (yellow) in adult mouse dLGN.
In a second set of synaptogenic studies, we continue to define novel roles for a unique family of extracellular matrix proteins in synaptic development in the brain. This family of extracellular matrix molecules, termed unconventional (or non-fibrillar) collagens, has been found to direct synaptic differentiation and maturation at the neuromuscular junction (NMJ) — a large peripheral synapse between motoneurons and muscle fibers. Specifically, controlled proteolysis of several collagen molecules at the NMJ generates soluble peptides that exhibit unique bioactivities compared to the full-length molecule from which they are derived. These proteolytically released fragments of collagen molecules are termed ‘matricryptins’ and at the NMJ collagen-derived matricryptins have been shown to direct pre- and postsynaptic assembly and maturation. Based upon bio-activities of these matricryptin-releasing collagens at the NMJ, we are now asking whether similar collagens (or their matricryptins) are necessary and sufficient to induce the formation of central synapses. Why is this important? Besides advancing our basic knowledge of brain development, these families of ECM molecules are highly mutated in humans and many of these mutations cause unexplained neurological deficits (including schizophrenia, autism spectrum disorders, and epilepsy).