A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

Abstract

IntroductionThe nucleus accumbens (NAcc), a major component of the ventral striatum, is believed to play a large role in the pathology of schizophrenia; however, there has been little direct investigation of this region in individuals with schizophrenia. Current antipsychotics are thought to target the NAcc and reduce a striatal hyperdopaminergic state, which was implicated in schizophrenia by early imaging and pharmacological studies.1,2 However, recent and further advanced imaging studies capable of analyzing the subregions of the striatum suggested the NAcc may not show a hyperdopaminergic state as much as neighbouring striatal regions. 3,4 In agreement with this idea, a recent postmortem study reported unaltered protein levels of the rate-limiting dopamine synthesis enzyme tyrosine hydroxylase within the NAcc.5 However, protein expression of the vesicle glutamate transporter VGLUT2 was found to be increased, suggesting altered glutamatergic signalling within the NAcc. 6 In support of this finding, increased asymmetric synapses, representative of glutamatergic projections, have been observed within the core of the NAcc in individuals with schizophrenia.7 Furthermore, these synapses were observed to have reduced postsynaptic density area. Taken together, these recent studies suggest that altered glutamatergic neurotransmission to the NAcc is associated with schizophrenia pathology; however, further evidence characterizing the glutamatergic system within the NAcc in individuals with schizophrenia is required.The NAcc receives dense excitatory input from the thalamus, hippocampus, prefrontal cortex (PFC) and amygdala, regions strongly associated with glutamatergic alterations in schizophrenia pathology. Background:The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic altera tions in the NAcc of a large schizophrenia cohort. Methods: We performed immunoblots on postmortem NAcc samples from 30 individ uals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the Nmethyldaspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia. Results: Protein levels of glutamatergic re ceptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Further more, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions be tween these receptors in this brain region. Limitations: Investigation of these proteins in antipsychoticnaive individuals, in addition to the subregions of the NAcc an...

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“…Recent studies show that schizophrenic patients exhibit altered integration of distinct sensory modalities [ 103 , 104 ]. Although we are still far from the elucidation of mechanisms that cause schizophrenia, a role for the NMDA receptor has been suggested [ 105 ]. Experiments in rats clearly show that NMDA receptor antagonists can generate a dose-dependent selective impairment in multisensory information processing [ 106 ].…”

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“…In brief, samples containing 5 µg of protein were resolved in 4-20% TGX precast gels (Bio-Rad, Australia), and subsequently transferred to a PVDF membrane (Bio-Rad). This loading concentration was determined to be in the linear range of a standard curve (Lum et al, 2017). The membranes were incubated in the primary polyclonal antibodies at the following concentrations: anti-mGluR1α (1:15 000; DH510, Cell Signalling), anti-mGluR5 (1:5000; ab29170, Abcam), anti-Norbin (1:7500; Ab130507; Abcam), anti-Homer1a (1:5000; sc-8922, Santa Cruz) and anti-Homer1b/c (1:10 000; Ab97593; Abcam).…”

In Vivo Non-radioactive Assessment of mGlu5 Receptor-Activated Polyphosphoinositide Hydrolysis in Response to Systemic Administration of a Positive Allosteric Modulator

“…This raises the interest on how expression and function of mGlu5 receptors change during CNS development ( Minakami et al, 1995 ; Casabona et al, 1997 ), in association with learning and memory processes ( Riedel et al, 2000 ), in response to stress ( Zuena et al, 2008 ; Yim et al, 2012 ), and under pathological conditions. Abnormalities in the expression or function of mGlu5 receptors have been associated with schizophrenia ( Ohnuma et al, 1998 ; Gupta et al, 2005 ; Matosin et al, 2013 , 2015 ; Fatemi and Folsom, 2015 ; Lum et al, 2017 ; Zurawek et al, 2017 ), focal cortical dysplasia ( DuBois et al, 2016 ), absence epilepsy ( D’Amore et al, 2015 ), Down’s syndrome ( Iyer et al, 2014 ), neuropathic pain ( Lin et al, 2015 ), Fragile-X syndrome, and other types of monogenic autism ( Huber et al, 2002 ; Bear et al, 2004 ; Giuffrida et al, 2005 ; Ronesi et al, 2012 ; Pignatelli et al, 2014 ).…”