Balancing stability and plasticityperturbations of extracellular matrix and inhibitory activity in the mature grid cell network

Abstract

Our brain is constantly challenged to learn new skills and form new memories, while at the same time having to retain stabile memories of previous experiences. One component contributing to stability is a specialized form of protein structures named perineuronal nets (PNNs). Late in development, PNNs emerge around subpopulations of neurons, wrapping them like a fishnet with holes for synaptic contacts. The appearance of PNNs coincide with a drastic decrease in synaptic plasticity, thus diminishing the brains ability to rewire and change. However, it is unknown if this phenomenon is important for our sense of space. In this thesis, I have investigated the role of PNNs for an area of the brain that is essential for navigation and spatial memory, the medial entorhinal cortex (MEC). Grid cells in MEC are active in highly specific triangular firing patterns, resembling coordinates on a map. I show that MEC express high levels of PNNs in adult rodents, indicating that there is little plasticity in the MEC network. Furthermore, when recording from grid cells in rats with PNNs removed, I found that PNNs are important for stabilizing the activity pattern of grid cells, particularly when rats explored a new environment for the first time. It is likely that PNNs regulate the activity of neurons that directly inhibit grid cells and therefore help to maintain their timing and activity levels, thus also the specificity of their activity patterns. Lastly, I went deeper into exploring the grid cell pattern. Grid cell activity is suggested to be dependent on brainwaves of a particular frequency. By using optogenetics to disrupt the source of rhythmic brainwaves in MEC while simultaneously recording grid cells, I falsified this hypothesis. This finding challenges several theoretical models used to explain grid cell activity and calls for alternative theories of how this remarkable pattern occurs. Overall, this work reveals new mechanisms at play for maintaining a stable sense of space.