REVIEW published: 21 November 2019 doi: 10.3389/fpsyt.2019.00835 Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type? Alexei M. Bygrave 1, Kasyoka Kilonzo 2, Dimitri M. Kullmann 3, David M. Bannerman 4 and Dennis Kätzel 2* 1 Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States, 2 Institute of Applied Physiology, Ulm University, Ulm, Germany, 3 UCL Queen Square Institute of Neurology, University College London, London, United Kingdom, 4 Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom Hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs), whether caused by endogenous factors like auto-antibodies or mutations, or by pharmacological or genetic manipulations, produces a wide variety of deficits which overlap with—but do not precisely match—the symptom spectrum of schizophrenia. In order to understand how NMDAR hypofunction leads to different components of the syndrome, it is necessary to take into account which neuronal subtypes are particularly affected by it in terms of detrimental Edited by: functional alterations. We provide a comprehensive overview detailing findings in rodent Bernat Kocsis, Harvard Medical School, models with cell type–specific knockout of NMDARs. Regarding inhibitory cortical cells, United States an emerging model suggests that NMDAR hypofunction in parvalbumin (PV) positive Reviewed by: interneurons is a potential risk factor for this disease. PV interneurons display a selective Margarita Behrens, Salk Institute for Biological Studies, vulnerability resulting from a combination of genetic, cellular, and environmental factors United States that produce pathological multi-level positive feedback loops. Central to this are two Vasileios Kafetzopoulos, antioxidant mechanisms—NMDAR activity and perineuronal nets—which are themselves Harvard Medical School, United States impaired by oxidative stress, amplifying disinhibition. However, NMDAR hypofunction *Correspondence: in excitatory pyramidal cells also produces a range of schizophrenia-related deficits, in Dennis Kätzel particular maladaptive learning and memory recall. Furthermore, NMDAR blockade in the [email protected] thalamus disturbs thalamocortical communication, and NMDAR ablation in dopaminergic Specialty section: neurons may provoke over-generalization in associative learning, which could relate to the This article was submitted positive symptom domain. Therefore, NMDAR hypofunction can produce schizophrenia- to Schizophrenia, related effects through an action on various different circuits and cell types. a section of the journal Frontiers in Psychiatry Keywords: schizophrenia, psychosis, N-methyl-D-aspartate receptor, N-methyl-D-aspartate receptor hypofunction, Received: 29 July 2019 parvalbumin, ketamine, MK-801, catatonic schizophrenia Accepted: 21 October 2019 Published: 21 November 2019 Citation: INTRODUCTION: THE GLUTAMATE HYPOTHESIS Bygrave AM, Kilonzo K, Kullmann DM, Bannerman DM and OF SCHIZOPHRENIA Kätzel D (2019) Can N-Methyl-D- Schizophrenia is characterized by a wide range of symptoms, classically grouped into positive Aspartate Receptor Hypofunction in Schizophrenia Be Localized (hallucinations, delusions, disordered thought), negative (social withdrawal, anhedonia, apathy), to an Individual Cell Type? and cognitive (deficits of attention, working memory, cognitive flexibility) domains1 ( , 2). Despite Front. Psychiatry 10:835. decades of research, the circuit basis of schizophrenia remains elusive, hampering progress in doi: 10.3389/fpsyt.2019.00835 diagnosis and treatment. Frontiers in Psychiatry | www.frontiersin.org 1 November 2019 | Volume 10 | Article 835 Bygrave et al. NMDAR Hypofunction in Schizophrenia No major breakthrough has been made in drug discovery NMDARs causes some or all of the symptoms of schizophrenia for schizophrenia treatments since the introduction of the (11–13). NMDAR hypofunction may be a precursor to deficits most effective atypical antipsychotic clozapine in 1971 3( , 4). in synaptic plasticity which have also been strongly linked to All antipsychotic drugs currently approved for schizophrenia the disorder (14). The core question for preclinical research in therapy have in common that they decrease signaling through this context is whether the NMDAR itself, or molecules that dopamine D2 receptors (D2Rs), and are most effective on positive affect its activity, are appropriate drug targets in established symptoms. However, negative and cognitive symptoms are largely schizophrenia. In turn, this can only be evaluated when the resistant to currently available medication, and even positive molecular phenomenon of NMDAR hypofunction is spelled symptoms respond only partially to the usual antipsychotic out mechanistically in the context of neural circuits—i.e. drugs, which in turn have significant side effects1 ( ). Therefore, when it is clarified which cell types in different brain different treatment targets—not relying on dopamine receptor structures are affected by NMDAR hypofunction and how antagonism—are urgently required. such altered signaling could cause different aspects of the In that context, the so-called “glutamate hypothesis”—the complex symptoms characterizing the disease. assumption that aberrant glutamatergic signaling is at the core of schizophrenia pathology—has sparked the most hope. The only two new specific targets tested in phase III clinical LINKING NMDAR HYPOFUNCTION TO trials in the last two decades in schizophrenia patients—the SCHIZOPHRENIA: GENETIC EVIDENCE metabotropic glutamate receptor type 2/3 (mGluR2/3) (5–8) and the glycine transporter 1 (GlyT1) (9), which affects levels The glutamatergic synapse, and in particular the NMDAR, is of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) one of the most prominent points of convergence of genetic co-agonist glycine—result from work pointing to abnormal risk factors for schizophrenia (15–17). Reduced expression of glutamatergic transmission in schizophrenia. A third target the obligatory NMDAR subunit GluN1 (also known as NR1; currently under investigation, D-amino acid oxidase (DAAO) encoded by GRIN1) and also of GluN2C (NR2C, encoded by (10), which also indirectly affects occupancy of the NMDAR GRIN2C) has been reported in post-mortem prefrontal cortex co-agonist site, is also based on the “glutamate hypothesis.” tissue of schizophrenia patients (18, 19). In addition, the GRIN2A A central pillar of this hypothesis is that hypofunction of and GRIN2B genes, encoding the GluN2A (NR2A) and GluN2B FIGURE 1 | Risk genes and molecules producing N-methyl-D-aspartate receptor (NMDAR) hypofunction and their effects on different cell types. Overview of three different categories of risk genes or NMDAR-antagonistic molecules which may produce NMDAR hypofunction (yellow boxes). The expression of different GluN2- subunits by different cell types may be a key driver of differential vulnerability of specific types of neurons in schizophrenia. The extent of GluN2B expression in interneurons and GluN2A expression in pyramidal cells is uncertain, as conflicting results exist in the literature and public databases, but they are likely to be small, at least in prefrontal cortex (see main text). Frontiers in Psychiatry | www.frontiersin.org 2 November 2019 | Volume 10 | Article 835 Bygrave et al. NMDAR Hypofunction in Schizophrenia (NR2B) subunit of the NMDAR respectively, are identified exome sequencing has revealed rare schizophrenia-related schizophrenia risk genes (Figure 1) (16, 17). damaging mutations in the gene encoding the tyrosine-kinase At least one GRIN2B risk allele (rs1805502) is associated FYN, which regulates NMDAR-trafficking (20, 21). with decreased expression of GluN1 in patients (18). Moreover, exome-sequencing studies revealed that rare damaging mutations in GRIN1, GRIN2A, and GRIN2B, LINKING NMDAR HYPOFUNCTION TO which are expected to cause NMDAR hypofunction directly, SCHIZOPHRENIA: PHARMACOLOGICAL are found in samples from schizophrenia patients, but not EVIDENCE controls (20, 21). Experiments in mice provide further support for a link between Support for the NMDAR hypofunction hypothesis of schizophrenia and hypofunction of GluN2A and GluN2B: Global schizophrenia also comes from the observation that ketamine ablation of Grin2A causes spatial working/short-term memory and phencyclidine (PCP), which are use-dependent non- deficits (without impairing basic spatial processing) (22). Further, competitive blockers of the NMDAR-channel, induce pharmacological blockade of GluN2B alone is sufficient to cause cognitive, negative, and positive symptoms of the disease (and behavioral abnormalities in rodents, in particular increased increased dopamine signaling) in humans and rodents (13). locomotor activity, which has been likened to psychosis (23, 24), as The finding that dopaminergic agonists, in contrast, may only well as reduced cognitive flexibility 25( ), but does not recapitulate reproduce positive symptoms is central to the proposal that the entire profile of schizophrenia, at least as far as the disease can NMDAR hypofunction is causally upstream of dopaminergic be modeled in rodents. For instance, pharmacological GluN2B aberrations in schizophrenia (11, 40, 41). Importantly though, blockade does not affect pre-pulse inhibition and may increase both PCP and ketamine have also been reported to act as motivation, working memory, processing speed, sustained agonists on D2Rs as well, they display