Living on the edge: The functional organization of metabotropic glutamate receptors at excitatory synapses

Abstract

The brain is a tremendously complex organ that consists of an intricate network of billions of nerve cells, also called neurons. Neurons are the main communicators of the brain and by sending signals from one neuron to the other they can trigger actions, ultimately underlying processes such as learning and memory. Neurons form synapses, which are special contact sites between two neurons where the communication takes place. Like in a handshake, but instead of greeting each other one neuron transfers a signal which is received by receptors on the other neuron. The signal activates the receptors which initiates a signaling cascade in the receiving neuron. The focus of this thesis is on metabotropic glutamate receptors (mGluRs), which are critical modulators of synaptic signaling on longer time scales. Synaptic signaling is tightly regulated and two aspects are essential for proper and efficient signal transmission: (1) the receiving receptors need to be positioned at the correct location, in close proximity to the released signal, to receive and respond, and (2) the activated receptors need to be rapidly deactivated in order to prevent overstimulation in the receiving neurons. This thesis aims at understanding how mGluR organization is regulated and how this tunes synaptic signaling. We used a combination of novel molecular tools, advanced imaging techniques and functional read-outs to directly examine this. We discovered that mGluRs are organized in dynamic clusters surrounding the area where signals are released, which is regulated by a specific part of the receptor. Furthermore, we show that Shank proteins regulate the uptake and recycling of mGluRs to prevent overstimulation after activation. Together, this thesis presents exciting novel insights in the functional organization of mGluRs at synapses, crucial for a better understanding of the brain in both health an disease.