Development Young Neurons Communicating Without Synapses

Demarque et al. investigated signaling to immature neurons and discovered tonic, spontaneous, and evoked currents mediated by neurotransmitters released through a nonconventional Ca²⁺-independent mechanism. Early in development--before synapses are formed--neurons contain neurotransmitter receptors, and research suggests that -aminobutyric acid (GABA) and glutamate, the principal neurotransmitters in the brain, modulate proliferation, migration, and morphological differentiation during development. The mechanisms by which neurons communicate before synapse formation, however, have remained unclear. Demarque et al. used whole-cell patch recording in embryonic and neonatal rat hippocampal slices to identify synaptically silent pyramidal cells that did not display traditional postsynaptic currents after stimulation; morphological reconstruction showed that basal dendrites were absent in these neurons. GABA receptor antagonists elicited an outward current, revealing tonic stimulation by GABA, whereas glutamate receptor antagonists had no electrical effect. Electrical stimulation elicited a 10- to 30-s current, which the authors named the early slow current (ESC); spontaneous ESCs were apparent during prolonged recording. Pharmacological analysis indicated that ESCs are mediated primarily by GABA_A receptors with a component from glutamate acting through N-methyl-D-aspartate (NMDA) receptors. The authors used transporter inhibitors to demonstrate that glutamate, but not GABA transporters, were active early in development. ESCs and tonic currents persisted in Cd²⁺-containing medium without added Ca²⁺, after treatment with botulinum toxin to block vesicle-mediated exocytosis, and in mutant mice that do not show vesicular secretion of neurotransmitter. These data suggest that immature neurons communicate through nonconventional release of neurotransmitters and that GABA spread during this developmental stage is facilitated by the lack of effective uptake mechanisms (see Owens and Kriegstein).

M. Demarque, A. Represa, H. Becq, I. Khalilov, Y. Ben-Ari, L. Aniksztejn, Paracrine intercellular communication by a Ca²⁺- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron 36, 1051-1061 (2002). [Online Journal]

D. F. Owens, A. R Kriegstein, Developmental neurotransmitters? Neuron 36, 989-991 (2002). [Online Journal]