Table 4.

Genetic animal models of NMDAR hypofunctionality.

Animal model	Positive symptom-like behavior	Negative symptom-like behavior	Sensorimotor gating deficits	Cognitive deficits	Structural and neurochemical changes	References
NR1 subunit knockout	• Hyperlocomotor activity, stereotypy, and decreased anxiety-like behavior in NR1 KD mice • Hyperlocomotor activity and stereotypy in GRIN1 compound het mice • Hyperlocomotor activity in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Blunted MK-801-induced hyperlocomotor activity in PV-specific NR1 KO mice • Hyperlocomotor activity in forebrain pyramidal cells-specific NR1 KO mice	• Reduced nest building, impaired social and sexual interactions in NR1 KD mice • Reduced sociability and sensitivity to NMDA-induced seizures in GRIN (D481N) mice • Disrupted nesting behavior in GRIN1 compound het mice • Social interaction deficits in CA3 NR1 KO mice • Anhedonia-like behavior in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Mating and nest-building deficits in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Anhedonia-like behavior in PV NR1 KD mice • Decreased self-care in forebrain pyramidal cells-specific NR1 KO mice	• Sensorimotor gating deficits in NR1 KD mice • Increased startle reactivity in GRIN1 (D481N) mice • Sensorimotor gating deficits in GRIN1 compound het mice • Sensorimotor gating deficits in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Sensorimotor gating deficits in mPFC and sensory cortex pyramidal cells-specific NR1 KO mice	• Cognitive inflexibility, abnormal selective attention, and spatial cognitive deficits in NR1 KD mice • Deficits in spatial recognition, spatial reference learning and memory in GRIN (D481N) mice • Deficits in spatial learning in GRIN1 compound het mice • Deficits in process of pattern separation and spatial working memory deficits in DG NR1 KO mice • Impairments in spatial memory, deficits in nonspatial memory and trace fear conditioning in forebrain pyramidal cells-specific NR1 KO mice • Deficits in avoidance task learning and memory formation in CA1 NR1 KD mice • Deficits in associative memory recall in CA3 pyramidal cells NR1 KO mice • Learning impairments in CA3 NR1 KO mice • Deficits in spatial working memory in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Deficits in spatial working, short- and long-term recognition memory in PV-specific NR1 KO mice • Deficits in working memory in PV-specific NR1 KO mice • Impairments in short-term memory in mPFC and sensory cortex pyramidal cells NR1 KO mice	• Increased axonal arborization in NR1 KD mice • Faster, premature developed projection neurons of the corpus callosum in NR1 KD mice • Altered dendritic differentiation, branching, and somatosensory pattern in NR1 KD mice • Reduced synapse number in an age-dependent manner in NR1 KD mice • Decreased NMDA currents, reduced 2-deoxyglucose uptake in the neocortex in NR1 KD mice • Increased amplitudes of auditory and visual ERPs in NR1 KD mice • Attenuated cortical and hippocampal theta-gamma phase coupling in NR1 KD mice • Increased dendritic length and reductions in 14-3-3epsilon and DISC1 protein expression in NR1 KD mice • Impaired hippocampal LTP in GRIN1 (D481N) mice • Striatal dopaminergic and serotonergic hyperfunction in GRIN1 compound het mice • Reduced firing rate from CA3 pyramidal cells during context-specific modulation in DG NR1 KO mice • Impaired LTP in DG NR1 KO mice • Lack of NMDA-mediated synaptic currents and LTP in forebrain pyramidal cells-specific NR1 KO mice • Impaired LTP at the C/A-CA3 synapse in CA3 pyramidal cells NR1 KO mice • Increased firing of cortical excitatory neurons with reduced neuronal synchrony in cortical and hippocampal GABAergic Interneurons NR1 KO mice • Increased gamma oscillation power and decreased theta oscillation power of LFP In hippocampus of PV-specific NR1 KO mice • Enhanced cortical gamma rhythm with impaired gamma rhythm induction after optogenetic drive of PV interneurons with decreased sensitivity to MK-801 on gamma oscillations and stereotypic behavior in PV-specific NR1 KO mice • Decreased D2R and GIRK2 expression in the forebrain from forebrain pyramidal cells-specific NR1 KO mice	Forrest et al., 1994; McHugh et al., 1996, 2007; Tsien et al., 1996; Iwasato et al., 1997; Mohn et al., 1999; Huerta et al., 2000; Kew et al., 2000; Rondi-Reig et al., 2001; Ballard et al., 2002; Cheli et al., 2002, 2006; Duncan et al., 2002, 2004; Nakazawa et al., 2002; Lee et al., 2005; Moy et al., 2006; Rajji et al., 2006; Bickel et al., 2007; Niewoehner et al., 2007; Labrie et al., 2008; Dzirasa et al., 2009; Halene et al., 2009; Belforte et al., 2010; Korotkova et al., 2010; Ramsey et al., 2011; Carlen et al., 2012; Rompala et al., 2013; Finlay et al., 2015; Tatard-Leitman et al., 2015; Bygrave et al., 2016
NR2A subunit knockout	• Hyperlocomotor activity in NR2A KO mice	• No changes observed	• No disruption in sensorimotor gating in NR2A KO mice	• Deficits in spatial learning, fear coding, and discrimination learning in NR2A KO mice	• Impairments in hippocampal LTP in NR2A KO mice • Reduced NMDAR EPSCSs and LTP in the CA3–CA1 synapse in hippocampal slices from NR2A KO mice	Carlsson and Lindqvist, 1963; Sakimura et al., 1995; Ito et al., 1997; Kiyama et al., 1998; Sprengel et al., 1998; Moriya et al., 2000; Brigman et al., 2008
NR2B subunit knockout	• Hyperlocomotor activity in CamKIIa NR2B KO mice	• No changes observed	• Enhanced startle responses to acoustic stimuli in NR2B het mice	• Impairments in spatial and nonspatial learning and memory in CamKIIa NR2B KO mice • Deficits in selective, short-term, spatial working memory in hippocampal pyramidal cells-specific NR2B KO mice	• Abolished LTD in the CA1 hippocampal neurons from NR2B KO mice • Diminished NMDAR EPSCs and LTP in the Fim-CA3 synapse from hippocampal slices of NR2B het mice • Decreased NMDAR-mediated EPSCs with accelerated decay kinetics and reduced cellular LTP in the hippocampus in hippocampal pyramidal cells-specific NR2B KO mice and CamKIIa NR2B KO mice	Kutsuwada et al., 1996; Ito et al., 1997; Takeuchi et al., 2001; von Engelhardt et al., 2008; Badanich et al., 2011
mGluR knockout	• Altered responses to stimulants in PV mGluR5 KO mice	• Increased compulsive-like behavior in PV-specific mGluR5 KO mice	• Abnormal sensorimotor gating in PV mGluR5 KO mice	• Memory impairments in PV mGluR5 KO mice	• Reduced numbers of PV interneuron density in PV mGluR5 KO mice • Decreased inhibitory currents in PV mGluR5 KO mice • Alterations in ERPs and brain oscillatory activity in PV mGluR5 KO mice • Deficient developmental switch from NR2B- to NR2A-containing receptors at synapses onto hippocampal CA1 pyramidal neurons and pyramidal primal visual cortical neurons in mGluR5 KO mice	Matta et al., 2011; Uzunova et al., 2014; Barnes et al., 2015
NRG1 and ErbB4 knockout	• Hyperlocomotor activity and increased motor coordination in NRG1 het mice • Hyperlocomotor activity in NRG1 het mice • Hyperlocomotor activity in ErbB4 het mice	• No changes observed	• Impairments in sensorimotor gating in NRG1het mice • Sensorimotor gating deficits in type III NRG1 het mice • Sensorimotor gating deficits in CNS-specific ErbB2 and ErbB4 dKO mice	• Impaired performance on delayed alternation task in type III NRG1 het mice • Disruption in cue utilization during Morris water maze in CNS-specific ErbB4 KO mice	• Deficits in subpopulations of cortical GABAergic interneurons in neuronal-specific ErbB4 het mice or type III NRG1 null mice • Enlarged lateral ventricles and decreased dendritic spines on hippocampal pyramidal neurons in NRG1 het mice • Reduced power of kainate-induced gamma oscillations in ErbB4 het mice • Reduced numbers of PV and CB interneuron density in the hippocampus and GABAergic interneurons in the cortex in ErbB4 het mice • Delayed postnatal motor development in CNS-specific ErbB4 KO mice • Decreased spine density in the cortex and hippocampus in CNS-specific ErbB2 and ErbB4 dKO mice • Thinning of myelin sheath of the corpus callosum, altered oligodendrocyte morphology, increased number of cells expressing differentiated oligodendrocytes, dopaminergic abnormalities in dominant negative ErbB4 mutant mice • Bath application of NRG1 reduces NMDAR-mediated currents in PFC pyramidal neurons • Increased expression of NRG1 and ErbB4 proteins upon chronic MK-801 administration in rats • NRG1-ErbB4 signaling may either suppress Src-mediated enhancement of synaptic NMDAR function or through upregulation of EAAC1	Gassmann et al., 1995; Erickson et al., 1997; Gerlai et al., 2000; Stefansson et al., 2002; Flames et al., 2004; Golub et al., 2004; Thuret et al., 2004; Gu et al., 2005; Roy et al., 2007; Ago et al., 2008; Chen et al., 2008; Barros et al., 2009; Fisahn et al., 2009; Feng et al., 2010; Pitcher et al., 2011; Yu et al., 2015
14-3-3 protein knockout	• Hyperlocomotor activity in 14-3-3 FKO mice • Hyperlocomotor activity in 14-3-3ζ KO mice • Enhanced anxiety-like behavior in 14-3-3ε het mice	• Deficits in social interaction in 14-3-3 FKO mice	• Deficits in sensorimotor gating in 14-3-3 FKO mice • Reduced sensorimotor gating in 14-3-3ζ KO mice	• Deficits in working memory and associative learning and memory in 14-3-3 FKO mice • Cognitive deficits in 14-3-3ζ KO mice • Weak defects in working memory in 14-3-3ε het mice	• Reduction in the NMDAR-mediated synaptic currents in CA1 pyramidal neurons in 14-3-3 FKO mice • Protein levels of NR1 and NR2A subunits are reduced in the PSD fraction of 14-3-3 FKO mice • Impaired LTP at hippocampal CA3-CA1 synapses in 14-3-3 FKO mice • Altered synaptic connectivity in the prefrontal cortical synapses in 14-3-3 FKO mice • Altered synaptic neurotransmission and plasticity in 14-3-3ζ KO mice • Abnormal neuronal migration and axonal guidance defects in the hippocampus in 14-3-3ζ KO mice • Increased levels of DA in striatum in 14-3-3ζ KO mice	Ikeda et al., 2008; Cheah et al., 2012; Ramshaw et al., 2013; Qiao et al., 2014; Foote et al., 2015; Xu et al., 2015