Local E/I Balance and Spontaneous Dynamics in Neuronal Networks

The emergence of spontaneous activity in the form of synchronized bursting events (SBE) is considered to play a crucial role in activity-dependent development of neuronal networks. As inhibition matures, the spatiotemporal structure of activity becomes increasingly influenced by the balance between excitation and inhibition (E/I). Moreover, intricate interactions between excitatory (ENs) and inhibitory (INs) neurons may arise during their activity-dependent structural differentiation. However, how the resulting spatial embedding of INs and ENs in a network impacts on the spatiotemporal structure of spontaneous activity at both local and global scales remains poorly understood. In this study, we examine whether the local fraction of INs in a network, likely affecting the local EI balance, influences the initiation and propagation of SBEs. To address this question, we utilize generic networks of cultured neurons, which serve as an experimentally accessible model system.We record spontaneous SBEs with microelectrode arrays and use genetic and immunocytochemical methods to identify ENs and INs in these networks. Additionally, we modulate the degree of neuronal clustering by chronically inhibiting or stimulating protein kinase C (PKC), an enzyme promoting neuronal migration1. Our morphometric and electrophysiological analyses reveal how INs are embedded in homogeneous versus strongly clustered networks and how they influence the respective activity dynamics. In our project, we further aim at investigating whether and how the activity-dependent interaction of neuronal migration, neurite outgrowth, and maturation of inhibition influences the modular structure and specific spatial distribution of ENs and INs. This contributes to a deeper understanding of the role of inhibition in the maturation of neuronal networks.