Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Abstract

Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

GluN2A Subunit-Containing NMDA Receptors Are the Preferential Neuronal Targets of Homocysteine

“…Several studies reported that HCY (Lipton et al, 1997; Ganapathy et al, 2011; Bolton et al, 2013), as well as its derivative, homocysteic acid, studied earlier (Provini et al, 1991; Kilić et al, 1992) is an agonist operating via the glutamate binding sites of the NMDARs. In addition, HCY at relatively high concentrations (above 1 mM HCY) can compete with glycine for the NMDAR co-agonist binding sites (Lipton et al, 1997).…”

“…In addition, HCY at relatively high concentrations (above 1 mM HCY) can compete with glycine for the NMDAR co-agonist binding sites (Lipton et al, 1997). Recently, effects of HCY at relatively high concentrations (up to 1 mM) on NMDA and glutamate activated currents transferred through the channels of recombinant NMDARs composed of the GluN1 and GluN2A, GluN1 and GluN2B or GluN1 and GluN2D subunits were studied (Bolton et al, 2013). It has been demonstrated, that HCY can differently modulate peak amplitude of currents activated by NMDA and glutamate and reduce NMDAR desensitization caused by NMDA and glutamate depending on GluN2 subunit compositions (Bolton et al, 2013).…”

“…Recently, effects of HCY at relatively high concentrations (up to 1 mM) on NMDA and glutamate activated currents transferred through the channels of recombinant NMDARs composed of the GluN1 and GluN2A, GluN1 and GluN2B or GluN1 and GluN2D subunits were studied (Bolton et al, 2013). It has been demonstrated, that HCY can differently modulate peak amplitude of currents activated by NMDA and glutamate and reduce NMDAR desensitization caused by NMDA and glutamate depending on GluN2 subunit compositions (Bolton et al, 2013). Thus, several groups suggested that neuronal NMDARs may represent an important target for the action of elevated HCY (Kim and Pae, 1996; Lipton et al, 1997; Ganapathy et al, 2011; Poddar and Paul, 2013).…”

Current and Emergent Treatments for Symptoms and Neurocognitive Impairment in Schizophrenia

“…Although management of diet and lifestyle is not sufficient of itself to control schizophrenia, nevertheless, attention to these aspects may optimize brain function, improve quality of life and reduce excess mortality [1, 2] commonly associated with schizophrenia. Efficacy of exercise in schizophrenia is supported by randomized, controlled clinical trials [3]Exercise-induced increases in hippocampal volume in schizophrenia are linked to improved short-term memory [4]Genetically based disturbances in folate metabolism may also be linked to negative symptoms [5], age of onset [6], and risk for weight gain [7]; metabolic syndrome [8]Elevated homocysteine levels [9, 10] may increase oxidative stress [11] and lead to inhibition of NMDAR-mediated neurotransmission [12]Genetic dysregulation of glutathione synthesis may also lead to increased brain oxidative stress [13]Treatment with folic acid + vitamin B12 may lead to improved negative symptoms in individuals with genetic alterations in folate absorption [14, 15] …”

“…Elevated homocysteine levels [9, 10] may increase oxidative stress [11] and lead to inhibition of NMDAR-mediated neurotransmission [12]…”