It is important to determine the mechanisms controlling the number of neurons in the nervous system. Previously, we reported that neuronal activity plays a central role in controlling neuron number in the neonatal hippocampus of rodents. Neuronal survival requires sustained activation of the serine-threonine kinase Akt, which is initiated by neurotrophins and continued for several hours by neuronal activity and integrin signaling. Here, we focus on the CA3 region to show that neuronal apoptosis requires p53. As in wild-type animals, neuronal death occurs in the first postnatal week and ends by postnatal day (P)10 in p53(-/-) mice. During this period, the CA3 region of p53(-/-) mice contains significantly lower numbers of apoptotic cells, and at the end of the death period, it contains more neurons than the wild type. At P10, the p53(-/-) CA3 region contains a novel subpopulation of neurons with small soma size. These neurons show normal levels of tropomyosin receptor kinase receptor activation, but lower levels of activated Akt than the neurons with somata of normal size. These results suggest that p53 is the key downstream regulator of the novel survival-signaling pathway that regulates the number of CA3 neurons in the first 10 days of postnatal life.