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Puhl M.D.,Harvard University | Puhl M.D.,Laboratory for Psychiatric and Molecular Neuroscience | Berg A.R.,Harvard University | Berg A.R.,Behavioral Genetics Laboratory | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015

Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists D-serine and glycine. Glycine transporter 1 knockdowns (GlyT1+/-) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR-/-) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1+/- mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR-/- mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1+/- mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR-/- mice with D-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source

Balu D.T.,Harvard University | Balu D.T.,Laboratory for Psychiatric and Molecular Neuroscience | Coyle J.T.,Harvard University | Coyle J.T.,Laboratory for Psychiatric and Molecular Neuroscience
Current Opinion in Pharmacology | Year: 2015

Schizophrenia is a severe psychiatric illness that is characterized by reduced cortical connectivity, for which the underlying biological and genetic causes are not well understood. Although the currently approved antipsychotic drug treatments, which primarily modulate dopaminergic function, are effective at reducing positive symptoms (i.e. delusions and hallucinations), they do little to improve the disabling cognitive and negative (i.e. anhedonia) symptoms of patients with schizophrenia. This review details the recent genetic and neurobiological findings that link N-methyl-D-aspartate receptor (NMDAR) hypofunction to the etiology of schizophrenia. It also highlights potential treatment strategies that augment NMDA receptor function to treat the synaptic deficits and cognitive impairments. © 2014 Published by Elsevier Ltd. Source

Balu D.T.,Harvard University | Balu D.T.,Laboratory for Psychiatric and Molecular Neuroscience | Coyle J.T.,Harvard University | Coyle J.T.,Laboratory for Psychiatric and Molecular Neuroscience
Brain Research | Year: 2011

The N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxyl-5- methyl-4-isoxazole-propionate receptor (AMPAR) are ionotropic glutamate receptors responsible for excitatory neurotransmission in the brain. These excitatory synapses are found on dendritic spines, with the abundance of receptors concentrated at the postsynaptic density (PSD). We utilized two genetic mouse models, the serine racemase knockout (SR-/-) and the glycine transporter subtype 1 heterozygote mutant (GlyT1+/-), to determine how constitutive NMDAR hypo- and hyperfunction, respectively, affect the glutamate receptor composition of the PSD in the hippocampus and prefrontal cortex (PFC). Using cellular fractionation, we found that SR-/- mice had elevated protein levels of NR1 and NR2A NMDAR subunits specifically in the PSD-enriched fraction from the hippocampus, but not from the PFC. There were no changes in the amounts of AMPAR subunits (GluR1, GluR2), or PSD protein of 95 kDa (PSD95) in either brain region. GlyT1+/- mice also had elevated protein expression of NR1 and NR2A subunits in the PSD, as well as an increase in total protein. Moreover, GlyT1+/- mice had elevated amounts of GluR1 and GluR2 in the PSD, and higher total amounts of GluR1. Similar to SR-/- mice, there were no protein changes observed in the PFC. These findings illustrate the complexity of synaptic adaptation to altered NMDAR function. © 2011 Elsevier B.V. Source

Takagi S.,Tokyo Medical and Dental University | Takagi S.,Laboratory for Psychiatric and Molecular Neuroscience | Balu D.T.,Harvard University | Balu D.T.,Laboratory for Psychiatric and Molecular Neuroscience | And 2 more authors.
Schizophrenia Research | Year: 2015

NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR. -/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR. -/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (Arc) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15. mg/kg; 5. days) treated adult wild-type mice. We found that in contrast to SR. -/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR. -/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR. -/- mice more accurately reflect NMDAR hypofunction in schizophrenia. © 2015 Elsevier B.V. Source

Ishiwata S.,Tokyo Medical and Dental University | Umino A.,Tokyo Medical and Dental University | Balu D.T.,Harvard University | Balu D.T.,Laboratory for Psychiatric and Molecular Neuroscience | And 3 more authors.
Journal of Neural Transmission | Year: 2015

In the hippocampus of mice lacking the gene for serine racemase (SR), a d-serine synthesizing enzyme, in the CaMKIIα-expressing neurons, we observed a significant decrease in the extracellular concentration of d-serine, a coagonist for the N-methyl-d-aspartate type glutamate receptor (NMDAR), and NMDAR hypofunction as revealed by diminished extracellular taurine concentrations after an intra-hippocampal NMDA infusion when compared to the wild type controls. Therefore, the neuronal SR could regulate the extracellular d-serine signaling responsible for NMDAR activation in the hippocampus. © 2015, Springer-Verlag Wien. Source

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