Pharmacological manipulation of GABA-driven activity in ovo disrupts the development of dendritic morphology but not the maturation of spinal cord network activity
Tóm tắt
In the adult nervous system, GABA acts as a major inhibitory neurotransmitter; however, at early stages of neurodevelopment, GABA receptor activation leads to membrane depolarization and accumulation of [Ca2+]i. The role of excitatory GABAergic neurotransmission in the development of the nervous system is not fully understood. In this study, we investigated the role of excitatory GABA-driven activity in regulating the dendritic morphology and network function in the developing chicken spinal cord. Both bicuculline, a GABA receptor antagonist, and muscimol, a GABA agonist, inhibit the generation of spontaneous network activity in the isolated spinal cord at E8 or E10, indicating that altering GABA receptor activation disrupts the generation of spontaneous network activity in the chicken spinal cord. Treatment of chicken embryos with bicuculline or muscimol between E5 and E8 (or between E8 and E10), inhibits the dendritic outgrowth of motoneurons when compared to vehicle-treated embryos. The inhibitory effect of bicuculline or muscimol on the dendritic morphology of motoneurons was likely due to inhibition of GABA-driven network activity since a similar effect was also observed following reduction of network activity by Kir2.1 overexpression in the spinal cord. The inhibitory effect of bicuculline or muscimol was not caused by an adverse effect on cell survival. Surprisingly, chronic treatment of chicken embryos with bicuculline or muscimol has no effect on the shape and duration of the episodes of spontaneous activity, suggesting that maturation of network activity is not altered by disruption of the dendritic outgrowth of motoneurons. Taken together, these findings indicate that excitatory GABA receptor activation regulates the maturation of dendritic morphology in the developing spinal cord by an activity-dependent mechanism. However, inhibition of dendritic outgrowth caused by disruption of GABA-driven activity does not alter the maturation of spontaneous electrical activity generated by spinal cord networks, suggesting that compensatory mechanisms can reverse any adverse effect of dendritic morphology on network function.
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