Research

/Research
Research 2018-04-25T12:10:01+00:00

Synapse Development and Disorders

Synapses go through stages of development to form fully functional units.  Synapse function can be altered or impaired at any of these stages, including

  • the initial formation of the synaptic junction. See our projects regarding Bassoon, Neuroligins and S-SCAM
  • the subsequent maturation of the synapse from a basically functioning unit (“release and detect”) to a synapse with specialized parameters designed for its exact purpose in the future network, including the correct balance between stability /plasticity and its exact strength. See our projects regarding Neuroligins and synapse maturation.
  • activity-dependent changes in synaptic strength. See our projects regarding Mover/TPRGL and its role in shaping synapse properties.

Aberrant synapse development can lead to disorders. See our project descriptions for the association of

  • Neuroligins with autism spectrum disorders
  • S-SCAM and Mover / TPRGL with schizophrenia
  • Rogdi with Kohlschütter-Tönz syndrome

Diving Into The Deep

A synapse can form when an axon meets a synaptogenic site on the correct dendrite.  At the presynaptic site, this involves the local accumulation of vesicles containing neurotransmitters and the assembly of a protein complex called the cytomatrix of the active zone. The cytomatrix of the active zone is a meshwork of large multi-domain scaffolding proteins that build a dynamic platform for vesicles to undergo excytosis, thus releasing neurotransmitters. Synaptic cell adhesion molecules span the synaptic cleft and interact with each other to control the accumulation and function of pre- and postsynaptic proteins.

BASSOON is one of these large (3938 amino acids) presynaptic scaffolding proteins. We are studying how it is delivered to nascent synapses as a prerequisite for active zone formation.

MOVER is a small protein (266 amino acids) found on synaptic vesicles. It is also called SVAP30, TPRGL, TPRG1L and FAM79a. Some synapses have Mover, while others don’t. We are studying which synapses exactly have high or low levels of Mover, and how Mover shapes the properties of synaptic transmission at specialized synapses, including hippocampal mossy fiber terminals and at the calyx of Held.

ROGDI is another small protein (287 amino acids). Mutations in human ROGDI cause a rare disease called Kohlschütter-Tönz syndrome. We found that ROGDI is a component of presynaptic nerve terminals, raising the possibility that the disease is caused by presynaptic malfunction.

NEUROLIGIN-1 is a postsynaptic transmembrane protein that controls presynaptic properties. One way of signaling across the synaptic cleft is a direct binding of Neuroligin-1 to its presynaptic ligands – the Neurexins. We hypothesize that Neuroligin-1 has additional ways of signaling into the presynaptic terminal, and that this signaling is essential for promoting presynaptic maturation.

S-SCAM is a postsynaptic scaffolding molecule. One of its functions is to recruit and activate a cell adhesion molecule called Neuroligin-1, thus allowing Neuroligin-1 to transmit signals across the synaptic cleft and initiate the accumulation of synaptic vesicles (Stan et al., 2010). We hypothesize that S-SCAM is required for synapse formation and maintenance on a more global level by controlling the accumulation of a large number of pre- and postsynaptic proteins.