Getting connected: the role of Sez6 family proteins in excitatory synapse development and maintenance

Munro KM1, Nash AN1, Teng KS-L1, Carrodus NL1,2, Barwood JM1,2, Fuller SJ1,2, Eroglu C3, Takeshima H4, Power J5 and Gunnersen JM1,2

  1. Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, 3010, Victoria, Australia.
  2. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Victoria, Australia.
  3. Duke University Medical Center, Durham, NC 27710, USA.
  4. Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
  5. Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, UNSW Australia, Sydney, 2052, NSW, Australia.

The development of efficient synaptic connections and their refinement and maintenance is vital for cognition. Altered expression and/or function of proteins in the Seizure-related 6 (Sez6) family is associated with cognitive disorders and mice lacking Sez6 throughout development exhibit fewer neocortical excitatory synapses. Whether Sez6 proteins are required in the adult brain to maintain excitatory synaptic function, and the extent to which the three Sez6 family members functionally compensate for each other, is not known. These questions are highly relevant to the clinical trials of β-site amyloid precursor protein cleavage enzyme 1 (BACE1) inhibitors for Alzheimer’s disease because Sez6 proteins are major BACE substrates and, therefore, likely to contribute to mechanism-based side effects when BACE1 is chronically inhibited. The results of behavioural, electrophysiological, morphological and biochemical analyses of Sez6 family triple knockout and Sez6 conditional knockout mice reveal that Sez6 proteins are important, not only for synapse development but also for maintaining excitatory synapse structure and function in the adult brain.