Between birth and the age of 6, synapses form at a furious rate. During pubescence and adolescence, a period known as competitive elimination occurs, with extensive synaptic pruning and restructuring. Only about half to two-thirds of the synapses present in childhood survive into adulthood.

In particular, adolescence is a critical time period for the pruning of asymmetric excitatory glutamate synapses and for the proliferation of inhibitory GABA synapses, as well as the elaboration of glutamatergic dendrites as targets of GABA neurotransmission. Dopaminergic innervation of the prefrontal cortex also substantially increases during this time period.

An appropriate balance of excitatory-inhibitory synapses is essential to proper late-stage brain maturation. Thus, any aberrations that occur in this process may confer risk for disorders related to brain dysconnectivity.

Normally, when glutamate synapses are active, their NMDA receptors trigger an electrical phenomenon known as long-term potentiation, or LTP. LTP leads to structural and functional changes of the synapse that make neurotransmission more efficient, sometimes called "strengthening" of synapses. These changes include increasing the number of AMPA receptors, which are important for mediating excitatory neurotransmission and depolarization at glutamate synapses.

More AMPA receptors can mean a "strengthened" synapse. Frequently used synaptic connections develop recurrent LTP and consequential robust neuroplastic influences, thus strengthening them. Infrequently used synaptic connections have less active NMDA receptors, and thus fewer AMPA receptors and long-term depression. During the competitive elimination stage, "strong" synapses with efficient NMDA neurotransmission and many AMPA receptors survive, whereas "weak" synapses with few AMPA receptors may be targets for elimination. This shaping of the brain's circuits normally allows the most critical synapses to survive, while inefficient and rarely utilized synapses are eliminated.

Abnormalities in the NMDA receptor may jeopardize this essential process. The NMDA receptor is comprised of 4 subunits. During brain development, the subunit composition of NMDA receptors switches. The timing of the switching differs by brain region and may coincide with risk windows. Specifically, during neurodevelopment, NMDA receptors in the hippocampus and cortex undergo a switch in subunit composition, including a change in the ratio of GluN2B to GluN2A subunits. Ideally, the changes in subunit composition make the receptor more suitable for optimal timing of firing, which should translate into more efficient neurotransmission. Aberrations in this switching process can lead to abnormalities in the mature NMDA receptor subunit profile, would could affect LTP and LDP LTD such that pruning in adolescence becomes random and neuronal dysconnectivity occurs.

References

Feinberg I. J Psychiatr Res 1982-83;17:319-34.

Insel TR. Nature 2010;468:187-93.

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.

NEI Member Animation: NMDA Receptors and the Proposed Origins of Schizophrenia A major current hypothesis for the cause of schizophrenia proposes that glutamate activity at NMDA receptors is hypofunctional due to abnormalities in the formation of NMDA synapses during neurodevelopment.