Abstract
BackgroundNeonatal astrocytes are diverse in origin, and undergo dramatic change in gene expression, morphological differentiation and syncytial networking throughout development. Neonatal astrocytes also play multifaceted roles in neuronal circuitry establishment. However, the extent to which neonatal astrocytes differ from their counterparts in the adult brain remains unknown.ResultsBased on ALDH1L1-eGFP expression or sulforhodamine 101 staining, neonatal astrocytes at postnatal day 1–3 can be reliably identified in hippocampal stratum radiatum. They exhibit a more negative resting membrane potential (VM), −85 mV, than mature astrocytes, −80 mV and a variably rectifying whole-cell current profile due to complex expression of voltage-gated outward transient K+ (IKa), delayed rectifying K+ (IKd) and inward K+ (IKin) conductances. Differing from NG2 glia, depolarization-induced inward Na+ currents (INa) could not be detected in neonatal astrocytes. A quasi-physiological VM of −69 mV was retained when inwardly rectifying Kir4.1 was inhibited by 100 μM Ba2+ in both wild type and TWIK-1/TREK-1 double gene knockout astrocytes, indicating expression of additional leak K+ channels yet unknown. In dual patch recording, electrical coupling was detected in 74 % (14/19 pairs) of neonatal astrocytes with largely variable coupling coefficients. The increasing gap junction coupling progressively masked the rectifying K+ conductances to account for an increasing number of linear voltage-to-current relationship passive astrocytes (PAs). Gap junction inhibition, by 100 μM meclofenamic acid, substantially reduced membrane conductance and converted all the neonatal PAs to variably rectifying astrocytes. The low density expression of leak K+ conductance in neonatal astrocytes corresponded to a ~50 % less K+ uptake capacity compared to adult astrocytes.ConclusionsNeonatal astrocytes predominantly express a variety of rectifying K+ conductances, form discrete cell-to-cell gap junction coupling and are deficient in K+ homeostatic capacity.
Highlights
Neonatal astrocytes are diverse in origin, and undergo dramatic change in gene expression, morphological differentiation and syncytial networking throughout development
Identification of neonatal astrocytes in hippocampal stratum radiatum Lack of astrocytic stage-specific markers remains a challenge for the lineage tracing of astrocytes in embryonic and neonatal stages
We show that the passive behavior of neonatal astrocytes is solely attributable to gap junction coupling (Fig. 3)
Summary
Neonatal astrocytes are diverse in origin, and undergo dramatic change in gene expression, morphological differentiation and syncytial networking throughout development. Neonatal astrocytes have been traditionally viewed as immature astrocytes undergoing extensive changes in cell proliferation, establishment of spatially distinct domains, integration into syncytial network through gap junction coupling, wrapping of blood vessels as part of the blood brain. After a short dormant period [4], the second wave of astrogliogenesis mainly produces astrocytes through symmetric division of differentiated astrocytes and to a less extent asymmetric division of NG2 glia [5, 18]. Whether neonatal astrocytes are strongly electrically coupled as has been observed in the adult brain. Information from this critical early developmental stage is essential for our further understanding of the role of neonatal astrocytes in the developing brain
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