Increased synaptic facilitation and exploratory behavior in mice lacking the presynaptic protein Mover

Abstract

In vertebrates and invertebrates, neurotransmitter release relies on a highly conserved molecular machinery. A surprisingly small number of presynaptic proteins evolved specifically in vertebrates. How they expand the power or versatility of the conserved core machinery is unclear. One of these vertebrate-specific proteins, called Mover / TPRGL / SVAP30, is heterogeneously expressed throughout the brain, suggesting that it adds special functions to subtypes of presynaptic terminals. In this study we generated Mover knockout mice to investigate the role of Mover from synaptic transmission to behavior. Deletion of Mover did not affect synaptic transmission at CA3 to CA1 synapses. In contrast, Mover deficient mice had strongly increased short-term facilitation at mossy fiber to CA3 synapses. This increase included frequency facilitation, a hallmark of mossy fiber terminal function. The effect was age- and Ca2+-dependent, and relied on the Kainate receptor/cAMP pathway in the mossy fiber terminals. Despite this change in presynaptic plasticity, the absence of Mover did not affect long-term spatial reference memory or working memory, but led to reduced anxiety. These discoveries suggest that Mover has distinct roles at different synapses. At mossy-fiber terminals, it acts to constrain the extent of presynaptic facilitation. Its role in activity-dependent neurotransmission could be necessary for normal anxiety responses. Significance StatementThe enormous increase in the complexity of brains during evolution is accompanied by a remarkably small number of new, vertebrate-specific presynaptic proteins. These proteins are unlikely to be essential for transmitter release, because invertebrate synapses do not need them. But what functions do they fulfill? We show that the vertebrate-specific protein Mover is involved in constraining the release of neurotransmitters in some synapses in the hippocampus, while not affecting others. We further demonstrate that the absence of this protein leads to decreased anxiety levels. Understanding the function of such a protein can help us further understand synaptic transmission, the specializations that are brought about in vertebrate synapses, and how this can help or hinder neurological or psychiatric disorders.