BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2

Citations Over TimeTop 10% of 2003 papers

Abstract

Spontaneous neural activity is a basic property of the developing brain, which regulates key developmental processes, including migration, neural differentiation and formation and refinement of connections. The mechanisms regulating spontaneous activity are not known. By using transgenic embryos that overexpress BDNF under the control of the nestin promoter, we show here that BDNF controls the emergence and robustness of spontaneous activity in embryonic hippocampal slices. Further, BDNF dramatically increases spontaneous co-active network activity, which is believed to synchronize gene expression and synaptogenesis in vast numbers of neurons. In fact, BDNF raises the spontaneous activity of E18 hippocampal neurons to levels that are typical of postnatal slices. We also show that BDNF overexpression increases the number of synapses at much earlier stages (E18) than those reported previously. Most of these synapses were GABAergic, and GABAergic interneurons showed hypertrophy and a 3-fold increase in GAD expression. Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K(+)/Cl(-) KCC2 co-transporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl(-) potential. Together, results indicate that both the presynaptic and postsynaptic machineries of GABAergic circuits may be essential targets of BDNF actions to control spontaneous activity. The data indicate that BDNF is a potent regulator of spontaneous activity and co-active networks, which is a new level of regulation of neurotrophins. Given that BDNF itself is regulated by neuronal activity, we suggest that BDNF acts as a homeostatic factor controlling the emergence, complexity and networking properties of spontaneous networks.

Related Papers

• → Neurotrophins and Neuronal Plasticity(1995)1,932 cited
• → Molecular mechanisms underlying neural circuit formation(2009)75 cited
• → Mapping Functional Connectivity between Neuronal Ensembles with Larval Zebrafish Transgenic for a Ratiometric Calcium Indicator(2011)21 cited
• → Nature over Nurture: Functional neuronal circuits emerge in the absence of developmental activity(2022)6 cited
• → OptoMEA: A Platform for Analyzing Signaling Efficiency of Neuronal Circuits using Multi-Location Extracellular Electrophysiology, Optical Imaging and Optogenetics(2016)