Network function of early born glutamatergic neurons in health and disease

• Applicant: Professor Dr. Heinz Beck
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242919836

Cell type diversity classically reflects the available repertoire of neuronal functions. It is a major hallmark of cortical GABAergic cells, which can be subdivided into many functionally and morphologically distinct classes. Recent studies indicate that the phenotypic variety of GABAergic cells is rooted in their spatio-temporal embryonic origins. In contrast to the wealth of knowledge about GABAergic neuron subtypes, we know little about the diversity of the far more numerous glutamatergic neurons (~80% of the total population), which have been mostly viewed as identical functional units within a given cortical region. Recently, the Cossart group has found that an early temporal origin could delineate a distinct morpho-functional subtype of glutamatergic neuron in the CA3 region of the hippocampus. This study suggests that developmental origin is a major factor in the determination of distinct glutamatergic neuron subtypes. The key hypothesis of this proposal, based on substantial unpublished data, is that glutamatergic cells born early in embryogenesis display specific morpho-physiological properties and connectivity patterns that enable them to exert a specific role in orchestrating physiological or pathological network dynamics. In addition, we expect that these pioneer cells preferentially form interconnected microcircuits with a high functional network impact and that an early birthdate confers onto them a selective resistance to pathological insults. We believe that this hypothesis may extend to most, if not all brain structures and to many brain disorders. In a first attempt to generalize this potential general concept, we will test these hypotheses on three different families of glutamatergic neurons from two entirely different brain structures (hippocampus and subthalamic nucleus (STN)) : (1) semilunar DG granule cells, a poorly described canonical subtype of granule cells which exerts a powerful network influence, (2) the CA1 pyramidal cell, the most commonly studied subtype of glutamatergic neuron in the brain and (3) glutamatergic neurons from the STN, a region containing only glutamatergic neurons and known for its noxious role in Parkinsons disease (PD). We will use a transgenic mouse model in which glutamatergic neurons are labelled according to their age. To explore the individual contribution of early born glutamatergic neurons at network level, we will combine cutting edge genetic, optical, electrophysiological and mathematical approaches both in vitro and in vivo.Glutamatergic cell diversity will be analyzed in the context of two major common chronic brain disorders, temporal lobe epilepsy (TLE) and Parkinsons disease both of which have devastating consequences for the individual and for society. Analyzing complex network changes occurring in TLE and PD from the point of view of development, should unravel specific microcircuits that might preferentially act on pathological neuronal ensemble activity.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Participating Person: Professorin Rosa Cossart, Ph.D.