Professor of Developmental Neurobiology & Director
Phone: 0207 848 8655
Development of the cerebral cortex in health and disease
- Oscar Marin, Director
- Ian Andrew, Technician
- Sung Eun Bae, Lab Manager/Research Technician
- Giorgia Bartolini, Research Assistant
- Kinga Bercsenyi, Research Associate
- Mi Da, Research Associate
- Hannah Dooley, Summer student
- Asha Dopplapudi, Lab Manager/Research Technician
- Randa Elsayed Elsayed, Technician
- Lynette Lim, Research Associate
- Alfredo Llorca, PhD Student
- Catarina Osorio, Research Associate
- Marian Otero Fernandez, Technician
- Veronique van den Berghe, Marie Curie Research Fellow
The neural assembly underlying the formation of functional networks in thecerebral cortex constitutes one of the most complex neuronal systems in the brain. Much of this complexity arises during development through the interaction of two distinct neuronal types, glutamatergic projection neurons and GABAergic interneurons. Pyramidal cells constitute approximately 80% of the neurons in the cortex and they specialize in transmitting information between different cortical regions and to other regions of the brain. Interneurons comprise a highly heterogeneous group of neurons that primarily contribute to local assemblies, where they provide inhibitory inputs and they shape different forms of synchronized oscillations.Our research largely concentrates on the analysis of the mechanisms controlling the the migration, final allocation and connectivity of cortical interneurons, although we are also interested in understanding the general principles regulating the development of other classes of cortical neurons. We believe that our research may contribute to understanding the etiology of some of the most devastating psychiatric disorders, such as autism or schizophrenia. Below you will find more information on our current research interests.
GABAergic interneurons constitute one of the most diverse groups of cells in the central nervous system. In the cerebral cortex, for example, the variability of interneurons is so large, and defining features so diverse, than it has even been suggested that they do not exist as distinct groups, but rather as a collection of cells with a continuous spectrum of characteristics. Despite this broad interpretation, current evidence suggest that cortical interneurons indeed belong to distinct neuronal populations (probably over 20 distinct cell types), which can be defined on the basis of their morphological, electrophysiological and neurochemical characteristics.Cortical interneurons originate from the subpallium, the region of the telencephalon that also give rise to the basal ganglia and the amygdala, among other structures. Genetic and fate mapping studies –primarily in the mouse– have revealed that most cortical interneurons are born in three regions of the subpallium, the medial ganglionic eminence (MGE), the caudal ganglionic eminence (CGE), and the preoptic area (POA).Work from several laboratories, including ours, has provided evidence suggesting that interneuron diversity in the telencephalon emerges as a consequence of the differential specification of progenitor cells, which are grouped in largely non-overlapping progenitor domains. We are currently performing additional fate mapping studies of specific progenitor domains in the subpallium to identify the precise origin of interneurons. In particular, we are developing new methods to trace the progeny of individual progenitor cells within the subpallium, with the aim of identifying the fate and destiny of clonally-related interneurons.
In the last few years, studies from different laboratories have demonstrated that a large number of cortical interneurons do not derive from the cortical ventricular zone, but instead are produced in the basal telencephalon and then migrate tangentially to the cerebral cortex. These results suggest that cortical projection neurons and interneurons follow different development programs. This finding has enormous implications for our understanding of the different pathologies of the development of the cerebral cortex, since it suggests that different genetic abnormalities could affect differentially both neuronal populations.In our laboratory, we are interested in understanding the molecular mechanisms that control the tangential migration of interneurons from the basal telencephalon to the cerebral cortex. We have extensively studied the migration of interneurons from the MGE to the cortex, and found that it involves the simultaneous activity of several chemorepulsive and chemoattractive factors.The mechanisms controlling the guidance of interneurons within the developing cortex are less understood. Cortical interneurons disperse tangentially through the cortex following two main routes of migration, initially avoiding the cortical plate. We are now trying to identify the mechanisms that control the dispersion of interneurons within the developing cortex, as well as the molecules that regulate their precise laminar allocation.
One of the most characteristic features of interneurons is their axonal arborization, because it greatly determines their contribution to information processing within cortical networks. So, different classes of cortical interneurons are specialized in targeting different subcellular domains in pyramidal cells. For example, basket cells typically synapse onto the soma of pyramidal cells, while chandelier cells target primarily the axon initial segment in these neurons. Despite the importance of these features, very little is known about the mechanisms regulating the connectivity of interneurons, in particular in relation to their axonal and dendritic morphology. For example, it has been described that basket cells primarily synapse onto pyramidal cells that receive similar inputs, while they tend to avoid those that belong to different circuitries. How is this controlled during development?Understanding the mechanisms that control the wiring of interneurons in the cerebral cortex may shed light into the etiology of psychiatric disorders. For example, we have recently found that the schizophrenia susceptibility gene Nrg1 and its ErbB4 receptor are required for the wiring of some cortical interneurons. In the mouse, loss of ErbB4 function in chandelier cells reduces the number of synapses these cells made, a finding that is strikingly similar to one of the most salient pathological features observed in individuals with schizophrenia. Our laboratory is currently exploring the role of other disease specific genes in the wiring of cortical interneurons.