Scientific Understanding of Consciousness
Synaptogenesis induced by GABA in the Developing Mouse Cortex
Science 02 Sep 2016: Vol. 353, Issue 6303, pp. 1037-1040
De novo synaptogenesis induced by GABA in the developing mouse cortex
Won Chan Oh, et.al.
Max Planck Florida Institute for Neuroscience (MPFI), Jupiter, FL 33458, USA.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Max Planck Institute of Neurobiology, Martinsried 82152, Germany.
Dendrites of cortical pyramidal neurons contain intermingled excitatory and inhibitory synapses. We studied the local mechanisms that regulate the formation and distribution of synapses. We found that local γ-aminobutyric acid (GABA) release on dendrites of mouse cortical layer 2/3 pyramidal neurons could induce gephyrin puncta and dendritic spine formation via GABA type A receptor activation and voltage-gated calcium channels during early postnatal development. Furthermore, the newly formed inhibitory and excitatory synaptic structures rapidly gained functions. Bidirectional manipulation of GABA release from somatostatin-positive interneurons increased and decreased the number of gephyrin puncta and dendritic spines, respectively. These results highlight a noncanonical function of GABA as a local synaptogenic element shaping the early establishment of neuronal circuitry in mouse cortex.
The spatial arrangement of synapses determines the functional consequences of excitation and inhibition for synaptic integration, action potential generation, and repetitive activity. The initial processes of synapse formation are regulated by genetically programmed intrinsic mechanisms; later, synapses are further shaped by neuronal activity. Recently, a fine-scale optical approach using two-photon laser scanning microscopy and two-photon laser photoactivation revealed the processes of individual excitatory synapse formation in real time and the underlying signaling pathways in various brain regions such as the neocortex, hippocampus, and basal ganglia. However, the spatiotemporal mechanisms that govern activity-dependent de novo inhibitory synapse formation in a developing circuit remain poorly understood. Here, we used two-photon GABA photolysis to deliver spatiotemporally controlled patterns of GABA release in mouse dendrites and monitored how GABA release influences synapse formation. These activity-induced processes were visualized as gephyrin puncta and dendritic spines, which are inhibitory and excitatory synapse markers, respectively.
We first examined the total number of gephyrin puncta along the apical and basal dendrites in organotypic slice cultures during normal development. Both gephyrin puncta and dendritic spines rapidly increased between EP6–8 and EP10–12 [EP (equivalent postnatal) day = postnatal day at slice culturing + days in vitro], and these changes were not affected by Teal fluorescent protein fused to gephyrin (Teal-gephyrin) expression. A similar timeline of gephyrin puncta and dendritic spine formation was observed in vivo. These data indicate that the synapse-forming machinery operates efficiently in our experimental system. On the basis of these results, we focused on oblique dendrites localized >70 μm away from the soma at ages EP6 to EP8 for the following synaptogenesis experiments.
Our findings suggest that GABA sets the balance between inhibitory and excitatory synapses in early postnatal stages, laying the foundation for later circuit development. Because the developing dendrites in our study did not have predetermined spots for inhibitory or excitatory synapses, localization of axonal boutons may be an early step in the precise formation of inhibitory and excitatory circuits. Thus, early-depolarizing GABA action appears to promote local synaptogenesis and shapes cortical circuitry during brain development.
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