Rules of Engagement: Factors That Regulate Activity-Dependent Synaptic Plasticity During Neural Network Development

Abstract

Overproduction and pruning during development 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 experience, 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 propose that there are additional, equally important developmental processes that influence synaptic plasticity, including mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor activation. The goal of this review is to summarize what is known and what is not well understood about developmental changes in functional plasticity at glutamatergic synapses, and in the end, attempt to relate these changes to maturation of neural networks.

Gestational Methylazoxymethanol Exposure Leads to NMDAR Dysfunction in Hippocampus During Early Development and Lasting Deficits in Learning

“…During this period, the hippocampus undergoes synaptogenesis, neuronal dendritic arborization, synaptic pruning and remodeling, and maturation of circuitry (Crain et al, 1973;Hsia et al, 1998;Pokorny and Yamamoto, 1981;Swann et al, 1991). These processes, at least partially, rely upon synaptic activation and signaling through NMDARs (Stoneham et al, 2010). Evidence suggests that removal of NR3A from NMDARs is critical for synapse maturation and premature removal of NR3A-NMDARs could lead to detrimental effects in developing synapses (Perez-Otano et al, 2006;Roberts et al, 2009).…”

Adolescent nicotine induces persisting changes in development of neural connectivity

“…We (Ehlinger et al, 2012b) also reported that, while spine density was not increased in dentate after adolescent nicotine, the estimate of total number of spines was similarly increased by increased total dendrite length. The sequence noted by Ehlinger et al (2015), proliferation followed by regression in numbers, is characteristic of new synapse formation followed by stabilization, as summarized by Stoneham et al (2010). Presence of spines on new branches is presumptive evidence of synaptic contacts on those new branches, as spine formation depends upon excitatory synaptic input (Segal et al, 2003).…”

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

“…Neurons initially make contacts with many other neurons during development, followed by refinement or “pruning” of connections (Stoneham et al, 2010; Tessier and Broadie, 2009) possibly to enhance the signal to noise ratio during information processing (Collin and van den Heuvel, 2013; Yuste, 2011). Structural and functional remodeling of the circuitry takes place through activity-dependent synaptic maturation (Doll and Broadie, 2014; West and Greenberg, 2011).…”