Hyperpolarization of resting membrane potential causes retraction of spontaneous transients during mouse embryonic circuit development

Abstract

Abstract Spontaneous activity supports developmental processes in many brain regions during embryogenesis, and the spatial extent and frequency of the spontaneous activity are tightly regulated by stage. In the developing mouse hindbrain, spontaneous activity propagates widely and the waves can cover the entire hindbrain at E11.5. The activity then retracts to waves that are spatially restricted to the rostral midline at E13.5, before disappearing altogether by E15.5. However, the mechanism of retraction is unknown. We studied passive membrane properties of cells that are spatiotemporally relevant to the pattern of retraction in mouse embryonic hindbrain using whole-cell patch clamp and imaging techniques. We find that membrane excitability progressively decreases due to hyperpolarization of resting membrane potential and increased resting conductance density between E11.5 and E15.5, in a spatiotemporal pattern correlated with the retraction sequence. Retraction can be acutely reversed by membrane depolarization at E15.5, and the induced events propagate similarly to spontaneous activity at earlier stages, though without involving gap junctional coupling. Manipulation of [K(+)](o) or [Cl(-)](o) reveals that membrane potential follows E(K) more closely than E(Cl), suggesting a dominant role for K(+) conductance in the membrane hyperpolarization. Reducing membrane excitability by hyperpolarization of the resting membrane potential and increasing resting conductance are effective mechanisms to desynchronize spontaneous activity in a spatiotemporal manner, while allowing information processing to occur at the synaptic and cellular level.