Signaling events regulating the neurodevelopmental triad glutamate and secreted forms of β-amyloid precursor protein as examples

During development of the nervous system a common set of signal transduction pathways appear to regulate growth cone behaviors, synaptogenesis and natural cell death, three fundamental processes that comprise the 'neurodevelopmental triad'. Among the intercellular signals that coordinate the developmental triad in the mammalian brain are glutamate (the major excitatory neurotransmitter) and β-amyloid precursor protein (βAPP). Localization of ionotropic glutamate receptors to dendritic compartments allows for selective regulation of dendrite growth cones and spine formation by glutamate released from axonal growth cones and presynaptic terminals. Expression of particular subtypes of glutamate receptors peaks during a developmental time window within which synaptogenesis and natural neuronal death occur. Calcium is the preeminent second messenger mediating both acute (rapid remodelling of the microtubule and actin cytoskeletal systems) and delayed (transcriptional regulation of growth-related proteins; e.g., neurotrophins) actions of glutamate. The expression of βAPP in brain is developmentally regulated and it is expressed ubiquitously in differentiated neurons. βAPP is axonally transported and secreted forms of βAPP (sAPPs) are released from neurons in an activity-driven manner. Secreted APPs modulate neuronal excitability, counteract effects of glutamate on growth cone behaviors, and increase synaptic complexity. Acute actions of sAPPs appear to be transduced by cyclic GMP which promotes activation of K⁺ channels and reduces [Ca²⁺](i). Delayed actions of sAPPs may involve regulation of gene expression by the transcription factor NFκB. Finally, the striking effects of glutamate, neurotrophic factors, and sAPPs on synaptogenesis and neuronal survival in cell culture systems and in vivo suggest that each of these signals plays major roles in the process of natural cell death. The same signalling mechanisms that mediate adaptive regulation of neuroarehitecture during brain development appear to play prominent roles in maladaptive neurodegenerative processes in an array of disorders ranging from stroke to epilepsy to Alzheimer's disease.