Activity-dependent regulation of neuronal network excitability

Abstract

Electric aCtiVity plays a major role in the fine-tuning of neuronal connections during development. Since alterations in connectivity will in turn affect network activity, it is clear that neuronal network formation is the result of reciprocal interactions between the activity and the structure of the network. To investigate the role of electric activity in neuronal network development, we use primary cultures of dissociated fetal rat cerebral cortex. Following prolonged suppression of spontaneous electric activity in culture neuronal firing showed a strong increase in stereotyped burst firing, at the expense of variable non-burst firing. This mode of firing could be mimicked by blocking GABAergic inhibition, indicating that chronic suppression of electric activity induced a shift in the balance between excitation and inhibition, resulting in overexcitation. Chronic silencing induced a disproportionate decrease in GABA content, while the release of glutamate and aspartate was facilitated in early cultures. As a result, the ratio of stimulated release of excitatory versus inhibitory neurotransmitter was increased, in line with our hypothesis. Conversely, prolonged depolarization increased GABAergic staining intensity without affecting the density of GABAergic neurons. These data suggest that during brain development, compensatory mechanisms may operate, which serve to keep the level and/or pattern of electric activity within physiological limits. We propose a negative feed-back loop whereby electric activity stimulates the synthesis and release ofBDNF, which through trkB receptors on GABAergic neurons stimulates GABAergic network activity, restraining overall network activity.