Periodic Reporting for period 1 - GABACODEV (Role of GABAergic microcircuits with different embryonic origins in the orchestration of early cortical dynamics in the awake mouse pup)
Reporting period: 2015-04-01 to 2017-03-31
One way to understand the complexity of neural circuits in the normal and pathological brain is studying their emergence during development. Connectivity between neurons arises during a developmental period characterized by the onset of spontaneous coordinated activity between large numbers of maturing neurons. Such synchronous activity is thought to strengthen/fine-tune connections between cells and leading to the formation of functional networks, that will provide the necessary framework to process external information. Evidence suggests that synchronous activity is a crucial phenomenon supporting cognitive processes. On the pathological side both an increase and a decrease in neural synchrony appears to be associated to disorders with a strong neurodevelopmental component, namely epilepsy, schizophrenia and autism. Although a large number of studies have addressed the role of synchrony in adult cognitive processes, little attention has been given to the synchronous network mechanisms underlying neural circuit maturation in the normal and pathological brain. Recent progress has demonstrated that interneurons (GABAergic cells) have an important active role in the onset of coordinated activity leading to the maturation of cortical neural networks. Hence the aim of the present proposal have focused on the role of GABAergic microcircuits in the maturation of cortical circuits in vivo, to understand how cortical interneurons integrate and functionally contribute to neural networks maturation during development.
During the course of the present proposal we first addressed the time-dependent recruitment of GABAergic neurons into early patterns of cortical correlated activity during development in vivo, to clarify whether there is a specific interneuron subtype that function as leaders (driver hub cells) in the initiation of correlated neuronal activities and their different implications concerning network synchronization. To this aim we used a multidisciplinary approach that combined: two-photon calcium imaging of cells activity in awake animals, genetically modified mice to target interneurons according to their spatial or temporal origin, electrophysiological recordings to stimulate or record interneurons, and several neuroanatomical techniques to characterize interneurons subpopulations. Our results point out that already at early stages of development cortical interneurons form functional and spatial assemblies that shape developmental activity (Figure 1). In the following step we addressed whether spatial embryonic origin of interneurons shape their impact on network dynamics. We report that neocortical driver hub cells (synchronization masters) arise from a particular embryonic region, the Medial Ganglionic Eminence (MGE). Such cells display unique properties that make them key regulatory masters coordinating correlated activity in the maturing neocortex. In summary, work performed under the current proposal adds to our understanding regarding maturation of cortical circuits by linking interneurons development and circuit physiology and supposes a step forward towards the understanding of pathophysiology of neurological disorders. Results from the present proposal have been disseminated among the scientific community in several workshops and international conferences.
Our results suppose an important advance to understand the mechanisms that shape the maturity of cortical networks. They also provide the necessary background to follow up on the study of cortical development. Such knowledge is central to the study of pathological conditions where anomalous network synchronization has been observed (Uhlhaas and Singer, 2006). Most importantly, mutations in many genes have been associated with neurological disorders (e.g. autism) where no causal effect can be established on an individual or population level. An explanation for these neurological disorders still eludes researchers due to the lack of knowledge about the associated molecular mechanisms. This likely reflects the complexity of these diseases, in which the dynamics of network activity may be the common mechanism to which large numbers of small individual genetic contributions converge. Altogether, this study not only expanded the scientific basis to study the mechanisms of neuropsychiatric disorders with potential impact in diagnostics and therapeutics but also the outcome of this project has promoted scientific excellence in Europe and endorsed further research with possible medical and social impact.