Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

Abstract

Neurons in the brains of newborns are usually connected with many other neurons through weak synapses. This early pattern of connectivity is refined through pruning of many immature connections and strengthening of the remaining ones. NMDA receptors (NMDARs) are essential for the development of excitatory synapses, but their role in synaptic refinement is controversial. Although chronic application of blockers or global knockdown of NMDARs disrupts developmental refinement in many parts of the brain, the ubiquitous presence of NMDARs makes it difficult to dissociate direct effects from indirect ones. We addressed this question in the thalamus by using genetic mosaic deletion of NMDARs. We demonstrate that pruning and strengthening of immature synapses are blocked in neurons without NMDARs, but occur normally in neighboring neurons with NMDARs. Our data support a model in which activation of NMDARs in postsynaptic neurons initiates synaptic refinement.D uring early development in vertebrates, neurons in many parts of the nervous system form weak synapses with a large number of target cells (1-7). This early pattern of connectivity is refined through two processes: synapse elimination that removes many initial connections and synapse maturation whereby the remaining connections are strengthened (8,9). This refinement of immature synapses is essential for the formation of neural circuits, and provides the basis for behavioral development. Many studies, in particular those conducted at the neuromuscular junction, in the cerebellum and visual pathways, have demonstrated that activity plays a central role in synaptic refinement (10-12). However, the mechanisms of synaptic refinement remain incompletely understood. At the neuromuscular junction, silencing of synaptic transmission disrupted the refinement process (13,14). The role of synaptic transmission in the refinement of central synapses seems more complex. Although manipulations of presynaptic activity disrupted the refinement of connections in the visual pathway (15-17), some of the effects were independent of synaptic transmission (18,19).The vast majority of excitatory synapses in the brain use glutamate as neurotransmitter; synaptic transmission is usually mediated by AMPA receptors (AMPARs) and NMDA receptors (NMDARs) in postsynaptic neurons. NMDARs play an important role in the development of neural circuits. In the brains of neonates, glutamatergic synapses have few or no AMPARs, and synaptic transmission is primarily mediated by NMDARs (20-23). Activation of NMDARs by correlated activity is thought to be a key mechanism underlying synaptic refinement during development (24, 25). Consistent with this idea, chronic application of NMDAR antagonists or global knockdown of NMDARs disrupts developmental refinement of neuronal circuits in many parts of the brain (26-28). However, recent studies in the hippocampus have shown that single-cell deletion of NMDARs in newborn mice has no effect on the number or density of synaptic spines (29). These findings raised the...

Large-Scale Somatotopic Refinement via Functional Synapse Elimination in the Sensory Thalamus of Developing Mice

“…7). Adenylate cyclase 1, GluA3, and GluN1 are responsible for experiencedependent synaptic strengthening and/or elimination of lemniscal synapses in the VPM (Wang et al, 2011a;Wang et al, 2011b;Zhang et al, 2013). Therefore, these molecules may also contribute to the somatotopic refinement in the VPM.…”

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

“…As environmental input increases in postnatal life, competition for inputs yields the mass elimination of weak synapses (i.e. synaptic pruning), and the concurrent strengthening of remaining synapses [35]. This synaptic refinement helps establish the finely-tuned circuitry that characterizes a mature brain and depends on numerous mechanisms that parallel plasticity in the adult brain, including NMDAR-dependent AMPAR delivery to potentiated synapses, LTP, LTD, and the intact functioning of scaffold proteins [14,35-37].…”

“…synaptic pruning), and the concurrent strengthening of remaining synapses [35]. This synaptic refinement helps establish the finely-tuned circuitry that characterizes a mature brain and depends on numerous mechanisms that parallel plasticity in the adult brain, including NMDAR-dependent AMPAR delivery to potentiated synapses, LTP, LTD, and the intact functioning of scaffold proteins [14,35-37]. Developmental synaptic refinement occurs in a series of regionally hierarchical, overlapping waves, and is accompanied by the increasing expression of cellular and molecular “brakes” that stabilize synapses into mature circuits (see Box 3).…”

Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

“…Homer1a is in a prime position to impinge on synaptogenesis and synaptic pruning mechanisms during brain maturation given (i) its functional location at the glutamate PSD, (ii) its interactions with NMDA receptor complexes, (iii), the critical requirement of glutamate synapses in the refinement of neuronal connections during development [63-67], and (iv) the developmental impairments caused by disrupting glutamate receptor complexes [68, 69]. Postnatal forebrain expression of Homer1a increases from birth, peaking between 3 and 5 weeks [7].…”