Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Abstract

Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse

“…Previously, we demonstrated that chronic D-serine treatment at the dose used in the present studies corrected several cellular, molecular, and behavioral consequences of NMDAR hypofunction in SR 2/2 mice (Balu et al, 2013(Balu et al, , 2014. In the current studies, D-serine treatment caused a nonsignificant trend toward increased locomotor sensitization compared to untreated and vehicletreated animals, as hypothesized.…”

“…A recent genome-wide association study involving 38,000 subjects and over 100,000 controls revealed 108 gene loci that achieved genome-wide significance (Ripke et al, 2014). Notably, over a dozen of these risk genes directly interact with the NMDAR or are downstream mediators of its activity, including serine racemase (SR), which synthesizes the forebrain agonist for the NMDAR glycine modulatory site (GMS), D-serine. In addition, we have previously demonstrated that SR null mutant mice exhibit brain structural, neurochemical, and cognitive abnormalities closely resembling those described in schizophrenia (Balu et al, 2013;Puhl et al, 2014). Restoration of brain D-serine levels through exogenous treatment reverses these deficits (Balu et al, 2013).…”

Copy Number Variable MicroRNAs in Schizophrenia and Their Neurodevelopmental Gene Targets

“…Of the 26 predicted target genes of recurrent schizophreniarelated miRNAs identified in this study that were overrepresented in the top 20 gene sets (Figure 2), 8-CAPRIN1, KAL1, MAP2K7, MYO10, NTRK2, PRPF40A, SPRY3, and TSGA10-are differentially expressed in human dorsolateral prefrontal cortex (27). NTRK2 (known sometimes as TrkB), encoding a brain-derived neurotrophic factor receptor, also has altered levels in brains with schizophrenia (46) and is involved in dendritic spine morphogenesis (40). Additionally, one of the three genes predicted to be targeted by two miRNAs, hsa-miR-3179 and hsa-miR-3180-3p overlapped by 16p13.11 CNVs (47), was SYNGAP1, a gene implicated in autism, intellectual disability, and schizophrenia (48)(49)(50).…”

“…To minimize false positive targets, we adopted a high level of stringency and considered only gene targets predicted by at least two of three established prediction tools, treating case and comparison cohorts equally. Although imperfect, the integration of more than one prediction method tends to balance out the precision and recall, resulting in better accuracy and coverage of predictions (40). As a result of these factors, true target genes of the miRNAs observed were likely missed.…”

“…Predicted gene targets driving these results included CAPRIN1 (36,37), MYO10 (38), NEDD4 (39), NTRK2 (40), PAK2 at 3q29 (41), and RHOA (3). After correcting for multiple testing, none of the overrepresentation analyses had significant p values.…”