Ontogeny of the N-Methyl-D-Aspartate (NMDA) Receptor System and Susceptibility to Neurotoxicity

Abstract

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Activation of NMDARs is essential for long-term potentiation and spatial learning and memory (Malenka and Bear, 2004), and NMDAR blockade results in impaired synaptic plasticity manifested as adverse effects on learning and memory (Sakimura et al, 1995;Shimizu et al, 2000). It has been shown that higher doses of ketamine can induce neuroapoptosis in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007b;Wang et al, 2006) during early development. In agreement, we have previously reported that ketamine induces motor neuron toxicity in zebrafish embryos .…”

“…Reports also show that exposure of the developing brain to a clinically relevant cocktail of anesthetics that has both NMDA antagonist and GABA mimetic properties results in an extensive pattern of neuroapoptosis, and subsequent cognitive deficits (Olney et al, 2002b). Several reports have illustrated that ketamine can induce neuronal apoptosis when administered in high doses and/or for prolonged durations during susceptible periods of development in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007a;Wang et al, 2006) and these effects can manifest on later disruptions in cognitive function (Paule et al, 2011). To minimize risks to children exposed to anesthesia, it is paramount to understand how anesthetic drugs affect the developing nervous system and whether those effects can be ameliorated or prevented.…”

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

“…In the immature rat brain, blockade of NMDA receptors for only a few hours during late fetal or early neonatal life increases the normal apoptotic neurodegeneration process (Ikonomidou et al, 1999). The 7-10 day window appears to be critical, with even brief exposure to NMDA receptor antagonists resulting in deleterious effects on CNS development and function (Haberny et al, 2002). Perinatal treatment with NMDA receptor antagonists suggests that neonatal abnormalities in specific brain substrates lead to a delayed, postpubertal emergence of significant (Gorter and De Bruin, 1992) or mild (Németh et al, 2002) spatial learning dysfunction.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…The essentiality of the MIE has been demonstrated in both animal and human studies investigating NMDA itself, NMDA receptors antagonists and mutant mice lacking NMDA receptor subunits (reviewed in Haberny et al, 2002;Rezvani, 2006 andGranger et al, 2011). NMDA systemically administered in rats, has been shown to potentiate cognitive functions (Rezvani, 2006).…”

“…Finally, depletion of both NR2A and NR2B in single neurons has shown alteration in synaptic development (Gray et al, 2011). Interestingly, during development, especially during postnatal days (PND) 7-14 in rodents, the central nervous system (CNS) exhibits increased susceptibility to toxic insults that affect NMDA receptors (Haberny et al, 2002). This increased susceptibility has been suggested to be related to the elevated expression of specific NMDA receptor subunits (Miyamoto et al, 2001).…”