THE ROLE OF HIPPOCAMPAL CAJAL-RETZIUS CELLS IN THE MATURATION OF THE HIPPOCAMPAL REGION

We aim to understand the role played by different cell types in the formation of cortical circuits in physiological as well as pathophysiological conditions. In fact, alterations in the mechanisms guiding the differentiation and migration of neurons as well as synaptogenesis can lead to severe network malfunctions and to debilitating neurodevelopmental disorders. The project focuses on understanding the role of hippocampal Cajal-Retzius cells in the maturation of the hippocampal region. Cajal-Retzius cells were discovered at the end of the 19th century by one of the founding fathers of Neuroscience - Ramon y Cajal - but they are still quite mysterious. Cajal-Retzius are crucial during prenatal development for the correct formation of the cortex, but then most of these cells die soon after birth. However, there is one specific part of the brain, the hippocampus (an area very important for learning, memory and spatial navigation), where these cells survive for a long time. For example, in a mouse, these cells survive for at least 3-5 months after birth. The question is: why are these cells surviving only in this area? We speculate that they play an important role in the maturation of the neuronal circuits fundamental for memory and spatial navigation. These features mature in mice, as well as in humans, only after birth, and they require several months or years to do so. With this grant we will be able to use different complementary approaches - from tracing of neuronal connections across brain regions, to in vivo recordings of neuronal activity to gene expression analysis - to understand what happens if these cells are artificially removed soon after the birth of the animals. How is the circuit changing? How is gene expression altered? Is the animal still able to learn a simple task? Answering these questions will help us to reach a better understanding of how neuronal circuits are established both in physiological as well as pathophysiological conditions.

The hippocampal region plays a major role in the encoding, association, consolidation and retrieval of memories. It creates spatial maps that animals use to navigate the environment. The circuits for these features are refined around birth as well as during the first weeks of postnatal development, in rodents, and years, in humans. The mechanisms guiding this maturation are activity-regulated, and disruptions in this activity are detrimental for the proper functioning of the network. Defining the development of the hippocampal circuitry during this fundamental period of maturation is critical to understand the network function in both normal development and in neurodevelopmental disorders. Studies on neocortical development have showed that specific cell types and specific circuits are critical for this early period of network maturation, and that their perturbation leads to long-lasting deficits. However, an in-depth analysis of the development of the hippocampal circuit formation is still lacking. Indeed, a specific cell type characterizing the hippocampus during postnatal development, Cajal-Retzius cells, has received little attention. Our data show that ablation of these cells at early postnatal stages affects the maturation of the hippocampus, with defects in protein expression levels, synaptic physiology, spine morphology and place cells function. To properly comprehend the role of CR cells in the circuit of the hippocampal region , much about these cells has yet to be revealed. Our aim is to study the integration of Cajal-Retzius cells in the circuit of the hippocampal region and understand how they contribute to its maturation. We propose a collaborative, ambitious and interdisciplinary approach combining state-of-the-art anatomical, physiological and molecular techniques, aiming to reveal the importance of these cells in physiological and pathophysiological development.