In the immature hippocampus, the giant depolarizing potentials (GDPs) are recurrent network-driven synaptic events generated by gamma-aminobutyric acid (GABA), which in neonatal life is depolarizing and excitatory. The GDPs enable a high degree of synchrony in immature neurons and participate in activity-dependent growth and synapse formation. To understand how human immunodeficiency virus type one (HIV-1) infection in the immature brain impairs brain growth and development, we studied the effects of HIV-1 envelope glycoprotein, gp120, a viral toxin shed in abundance by infected cells, on spontaneous occurring GDPs recorded in the CA3 pyramidal cells in neonatal (P2-P6) Sprague-Dawley rat hippocampal slices using whole-cell patch technique. Bath application of gp120 produced a sustained enhancement of GDP frequency in a concentration-dependent manner without affecting passive membrane properties, suggesting that the site of action is most likely on neural network, other than on the recorded neurons. The gp120-induced enhancement of GDPs was blocked by T140, a highly specific antagonist for the chemokine receptor, CXCR4, indicating the involvement of CXCR4 in the gp120-induced increase of GDPs. Bath application of stromal cell-derived factor-1alpha (SDF-1alpha), the only CXCR4 ligand, mimicked the effects of gp120 on GDPs, supporting the engagement of CXCR4 receptors in the gp120-induced increase of GDP occurrence. Further studies revealed the involvement of protein kinase A/C in the gp120-induced enhancement of GDPs. These results demonstrate that gp120 enhances GDPs in the neonatal rat hippocampus. This enhancement may cause an excessive increase in intracellular calcium and resultant neuronal injury, leading to retardation of the brain and behavioural development as seen in paediatric AIDS patients.