Rules of Engagement: Factors That Regulate Activity-Dependent Synaptic Plasticity During Neural Network Development EMILY T. STONEHAM 1,2, *, ERIN M. SANDERS 1,2, *, MOHIMA SANYAL 2 , AND THEODORE C. DUMAS 1,2, † 1 Molecular Neuroscience Department, 2 Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030 Abstract. Overproduction and pruning during develop- ment is a phenomenon that can be observed in the number of organisms in a population, the number of cells in many tissue types, and even the number of synapses on individual neurons. The sculpting of synaptic connections in the brain of a developing organism is guided by its personal experi- ence, which on a neural level translates to specific patterns of activity. Activity-dependent plasticity at glutamatergic synapses is an integral part of neuronal network formation and maturation in developing vertebrate and invertebrate brains. As development of the rodent forebrain transitions away from an over-proliferative state, synaptic plasticity undergoes modification. Late developmental changes in synaptic plasticity signal the establishment of a more stable network and relate to pronounced perceptual and cognitive abilities. In large part, activation of glutamate-sensitive N- methyl-D-aspartate (NMDA) receptors regulates synaptic stabilization during development and is a necessary step in memory formation processes that occur in the forebrain. A developmental change in the subunits that compose NMDA receptors coincides with developmental modifications in synaptic plasticity and cognition, and thus much research in this area focuses on NMDA receptor composition. We pro- pose that there are additional, equally important develop- mental processes that influence synaptic plasticity, includ- ing mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor acti- vation. The goal of this review is to summarize what is known and what is not well understood about developmen- tal changes in functional plasticity at glutamatergic syn- apses, and in the end, attempt to relate these changes to maturation of neural networks. Introduction The life cycle of vast numbers of plants and animals involves an early period of massive cell proliferation fol- lowed by a competition-based organism death, which max- imizes health of that generation and results in a stable population of organisms. Obvious examples include blooms of phytoplankton and egg laying by sea turtles. This ubiq- uitous process of overproduction and pruning can also be observed in cell number during embryonic, fetal, and neo- natal development of many tissue systems. Similar to or- ganism development, tissue development usually involves a competition between cells for space and resources. This idea has been applied in interesting ways to nervous systems (Turkewitz and Kenny, 1985; Edelman, 1993). Through activity-based refinement processes that regulate pro- grammed cell death, cell number is trimmed during the final maturation phase (Hutchins and Barger, 1998). The influ- ence of activity on cell survival or death during develop- ment is mediated in large part through synaptic transmission Received 16 November 2009; accepted 5 August 2010. * These authors contributed equally to this project. † To whom correspondence should be addressed, at Molecular Neuro- science Department, 4400 University Drive, MS 2A1, Fairfax, VA 22030; tdumas@gmu.edu Abbreviations: AC, adenylate cyclase; AMPA, -amino-3-hydroxyl-5- methyl-4-isoxazole-propionate; AP, action potential; CaM, calmodulin; CaMKII, calmodulin-dependent kinase II; EPSP, excitatory postsynaptic potential; HCN, hyperpolarization-activated cyclic nucleotide-gated cat- ion; I-1, inhibitory protein 1; LTD, long-term depression; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate; P, postnatal day; PKC, protein kinase C; PP1, protein phosphatase 1; PPF, paired-pulse facilitation; SC- CA1, Schaffer collateral synapse. Reference: Biol. Bull. 219: 81–99. (October 2010) © 2010 Marine Biological Laboratory 81 This content downloaded from 129.174.021.005 on July 06, 2017 10:53:43 AM All use subject to University of Chicago Press Terms and Conditions (http://www.journals.uchicago.edu/t-and-c).