Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Abstract

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

Keywords: CREB; D-serine; N-methyl-D-aspartate receptor; anti-NMDAR encephalitis; epigenomics; epilepsy; excitotoxicity; glutamate.

Figure 1

Regulation of neuroexcitatory receptor N-Methyl-D-Aspartate Receptor (NMDAR) in epilepsy.

Figure 2

NMDAR-mediated excitotoxicity in epilepsy. In neurons, the NMDAR channel is blocked by Mg²⁺ at neuronal resting membrane potential, and Mg²⁺ is removed when the membrane is depolarized. Activated NMDAR leads to calcium loading which will cause the activation of nNOS, calpain I, and mitochondrial permeability transformation (MPT) pore and eventually lead to neuronal death. Calpain I can cleave Bid and Bax, leading to the release of apoptosis-inducing factor (AIF) and cytochrome C from the mitochondria. Meanwhile, cytochrome C can induce the activation of caspase, and calpain I can also directly cleave and activate caspases, thus resulting in apoptosis. In addition, AIF is cleaved by calpain I to a tAIF, which translocates to the nucleus and induces DNA cleavage, thereby leading to apoptosis and parthanatos. Activation of calpain can cause lysosomal membrane permeability (LMP), which releases the toxic cathepsin, DNase II, and ROS, thereby resulting in LCD. Meanwhile, HSP70 and calpastatin can resist LMP. Increased Ca²⁺, ROS, RNS, and low ATP in mitochondrial matrix results in MPT which depends on the opening of mPTP. Cyclosporine A and 3-MA can block MPT. Ca²⁺ directly activates nNOS, which can catalyze NO and O₂⁻ to form ONOO⁻. ONOO⁻ damages DNA, thereby activating PARP1, resulting in parthanatos. PARP1 is involved in chromosomal stability, DNA repair, and inflammatory responses. PAR, the product of PARP1 activity, induces nuclear translocation of AIF and inhibits HK. Nuclear translocation of AIF requires the involvement of CypA, which binds to AIF and forms CypA-AIF complex after the release from mitochondria, thereby participating in DNA degradation and leading to parthanatos. ARH3 reduces PAR levels in the nucleus and cytoplasm and IDUNA reduces the release of AIF by binding to the PAR polymers and prevents PARP1-induced cell death. LCD, lysosomal cell death; HSP70, heat shock protein 70; HK, hexokinase.

Figure 3

NMDAR -Ca²⁺-CREB signaling pathways in neuroprotection. NMDAR activity can activate CREB-dependent gene expression. CREB must be phosphorylated at serine-133 in order to recruit its co-activator CREB binding protein (CBP). Phosphorylation of CREB is mediated by the fast-acting nuclear Ca²⁺/CaMK pathway and the slower acting, longer lasting Ras-ERK1/2 pathway, both of which are promoted by activation of synaptic NMDARs. (1) Nuclear Ca²⁺-CaM-CaMKIV/CaMKII-CREB: nuclear Ca²⁺-dependent CaMKIV/CaMKII phosphorylates CBP at serine-301. (2) ERK1/2-CREB: CBP is also phosphorylated by Ras-MEK-ERK1/2 pathway or CaMKII/PKC/PKA-ERK1/2 pathway. CREB phosphorylated at serine-133 recruits its CBP. In addition, nuclear translocation of TORC activity is a key step in CREB activation. (3) Ca²⁺-TORC-CREB: synaptic NMDAR-induced Ca²⁺ signals promote TORC import into the nucleus by CaN-dependent dephosphorylation. TORC acts at least in part by assisting in the recruitment of CBP to CREB. (4) Ca²⁺-CRTC1-CREB: CRTC1 dephosphorylates at Ser-151 and is recruited from cytoplasm to the nucleus, where it competes with FXR for binding to CREB and drives autophagy gene expression. (5) Ca²⁺-TRPC6-CREB: Ca²⁺ influx through TRPC6 activates CREB, an important transcription factor linked to neuronal survival. (6) PI3K-AKT-GSK3β-CREB.

Figure 4

Regulation of NMDARs by D-serine and glutamate. (1) Glutamate can directly act on NMDAR, and the glutamate-glutamine cycle is involved in the regulation of NMDAR. Glutamate-glutamine cycle: glutamate can be directly synthesized de novo by astrocytes or indirectly produced from glucose molecules through the actions of pyruvate dehydrogenase and astrocyte-specific enzyme pyruvate carboxylase in the brain. Meanwhile, extracellular glutamate can be transferred to astrocytes by ETTA2 (GLT-1) and then converted to glutamine by glutamine synthetase (GS). Glutamine is transported by SNAT-5 to the extracellular environment, where it can then be transferred to neurons by SNAT-1. In the neuron, glutamine is degraded by PAG into glutamate and ammonia. Glutamate enters the synaptic vesicles in the pre-synaptic neurons and then is released from the pre-synaptic membrane into the synaptic cleave. It directly acts on the NMDAR in the post-synaptic neurons, thus activating NMDAR. (2) In addition to glutamate, activation of NMDAR also requires the binding of D-serine at the glycine binding site. SR converts L-serine to D-serine in the neuron, while DAAO catalyzes the breakdown of d-serine in the astrocyte. D-serine is released from neurons by Asc-1, which mediates D-serine efflux in exchange for external amino acid substrates. L-serine can be directly synthesized de novo in astrocytes. Through orchestrated Asc-1 and ASCT1 subtypes, L-serine from astrocytes enters the neuron and is catalyzed by SR to produce D-serine.