A new model for developmental neuronal death and excitatory/inhibitory balance in hippocampus.

The nervous system develops through a program that produces neurons in excess and then eliminates approximately half during a period of naturally occurring death. Neuronal activity has been shown to promote the survival of neurons during this period by stimulating the production and release of neurotrophins. In the peripheral nervous system (PNS), neurons depends on neurotrophins that activate survival pathways, which explains how the size of target cells influences number of neurons that innervate them (neurotrophin hypothesis). However, in the central nervous system (CNS), the role of neurotrophins has not been clear. Contrary to the neurotrophin hypothesis, a recent study shows that, in neonatal hippocampus, neurotrophins cannot promote survival without spontaneous network activity: Neurotrophins recruit neurons into spontaneously active networks, and this activity determines which neurons survive. By placing neurotrophin upstream of activity in the survival signaling pathway, these new results change our understanding of how neurotrophins promote survival. Spontaneous, synchronized network activity begins to spread through both principle neurons and interneurons in the hippocampus as they enter the death period. At this stage, neurotransmission mediated by γ-aminobutyric acid (GABA) is excitatory and drives the spontaneous activity. An important recent observation is that neurotrophins preferentially recruit GABAergic neurons into spontaneously active networks; thus, neurotrophins select for survival only those neurons joined to active networks with strong GABAergic inputs, which would later become inhibitory. A proper excitatory/inhibitory (E/I) balance is critical for normal adult brain function. This balance may be especially important in the hippocampus where impairments in E/I balance are associated with pathologies including epilepsy. Here, I discuss the molecular mechanisms for survival in neonatal neurons, how these mechanisms change during development, and how they may be linked to degenerative diseases.