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Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice

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Abstract

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. d-serine is a crucial modulator of neuroplasticity, and decreased levels of d-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of d-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain d-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of d-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, d-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that d-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

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Abbreviations

NMDAR:

N-methyl-d-aspartate receptor

Srr:

Serine racemase

PPI:

Prepulse inhibition

MMN:

Mismatch negativity

References

  • Abel K, Waikar M, Pedro B et al (1998) Repeated testing of prepulse inhibition and habituation of the startle reflex: a study in healthy human controls. J Psychopharmacol 12:330–337

    CAS  PubMed  Google Scholar 

  • Aubert L, Reiss D, Ouagazzal A-M (2006) Auditory and visual prepulse inhibition in mice: parametric analysis and strain comparisons. Genes Brain Behav 5:423–431

    CAS  PubMed  Google Scholar 

  • Bado P, Madeira C, Vargas-Lopes C et al (2011) Effects of low-dose D-serine on recognition and working memory in mice. Psychopharmacology 218:461–470

    CAS  PubMed  Google Scholar 

  • Bak N, Mann J, Fagerlund B et al (2017) Testing a decades’ old assumption: are individuals with lower sensory gating indeed more easily distracted? Psychiatry Res 255:387–393

    CAS  PubMed  Google Scholar 

  • Balu DT, Li Y, Puhl MD et al (2013) Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A 110:E2400–E2409

    CAS  PubMed  PubMed Central  Google Scholar 

  • Basu AC, Tsai GE, Ma C-L et al (2009) Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry 14:719–727

    CAS  PubMed  Google Scholar 

  • Bendikov I, Nadri C, Amar S et al (2007) A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res 90:41–51

    PubMed  Google Scholar 

  • Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry 156:596–602

    CAS  PubMed  Google Scholar 

  • Cain CK, McCue M, Bello I et al (2014) d-Cycloserine augmentation of cognitive remediation in schizophrenia. Schizophr Res 153:177–183

    PubMed  PubMed Central  Google Scholar 

  • Calcia MA, Madeira C, Alheira FV et al (2012) Plasma levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 142:83–87

    PubMed  Google Scholar 

  • Cavuş I, Reinhart RMG, Roach BJ et al (2012) Impaired visual cortical plasticity in schizophrenia. Biol Psychiatry 71:512–520

    PubMed  PubMed Central  Google Scholar 

  • Cho S-E, Na K-S, Cho S-J, Kang SG (2016) Low d-serine levels in schizophrenia: a systematic review and meta-analysis. Neurosci Lett 634:42–51

    CAS  PubMed  Google Scholar 

  • Chou H-H, Twamley E, Swerdlow NR (2012) Towards medication-enhancement of cognitive interventions in schizophrenia. Handb Exp Pharmacol 81–111

  • Clemenson GD, Deng W, Gage FH (2015) Environmental enrichment and neurogenesis: from mice to humans. Curr Opin Behav Sci 4:56–62

    Google Scholar 

  • Couillard-Despres S, Winner B, Schaubeck S et al (2005) Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 21:1–14

    PubMed  Google Scholar 

  • Curzon P, Zhang M, Radek RJ, Fox GB (2011) The Behavioral assessment of sensorimotor processes in the mouse: acoustic startle, sensory gating, locomotor activity, rotarod, and beam walking. In: Buccafusco JJ (ed) Methods of Behavior Analysis in Neuroscience. CRC Press/Taylor & Francis, Boca Raton

    Google Scholar 

  • Daskalakis ZJ, Christensen BK, Fitzgerald PB, Chen R (2008) Dysfunctional neural plasticity in patients with schizophrenia. Arch Gen Psychiatry 65:378–385

    PubMed  Google Scholar 

  • Erickson MA, Ruffle A, Gold JM (2016) A meta-analysis of mismatch negativity in schizophrenia: from clinical risk to disease specificity and progression. Biol Psychiatry 79:980–987

    PubMed  Google Scholar 

  • Faul F, Erdfelder E, Lang A-G, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191

    Google Scholar 

  • Föcking M, Lopez LM, English JA et al (2015) Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia. Mol Psychiatry 20:424–432

    PubMed  Google Scholar 

  • Guercio GD, Bevictori L, Vargas-Lopes C et al (2014) D-serine prevents cognitive deficits induced by acute stress. Neuropharmacology 86:1–8

    CAS  PubMed  Google Scholar 

  • Guercio GD, Panizzutti R (2018) Potential and challenges for the clinical use of d-serine as a cognitive enhancer. Front Psychiatry 9:14

    PubMed  PubMed Central  Google Scholar 

  • Guercio GD, Thomas ME, Cisneros-Franco JM et al (2018) Improving cognitive training for schizophrenia using neuroplasticity enhancers: lessons from decades of basic and clinical research. Schizophr Res. https://doi.org/10.1016/j.schres.2018.04.028

  • Hashimoto A, Nishikawa T, Hayashi T et al (1992) The presence of free D-serine in rat brain. FEBS Lett 296:33–36

    CAS  PubMed  Google Scholar 

  • Hashimoto K, Engberg G, Shimizu E et al (2005) Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry 29:767–769

    CAS  Google Scholar 

  • Hashimoto K, Fukushima T, Shimizu E et al (2003) Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    CAS  PubMed  Google Scholar 

  • Ira E, Zanoni M, Ruggeri M et al (2013) COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. J Psychiatry Neurosci 38:366–380

    PubMed  PubMed Central  Google Scholar 

  • Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC (1996) Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci U S A 93:11962–11967

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kakegawa W, Miyoshi Y, Hamase K et al (2011) D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor. Nat Neurosci 14:603–611

    CAS  PubMed  Google Scholar 

  • Kandel ER, Dudai Y, Mayford MR (2014) The molecular and systems biology of memory. Cell 157:163–186

    CAS  PubMed  Google Scholar 

  • Kantrowitz JT, Epstein ML, Beggel O et al (2016) Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain 139:3281–3295

    PubMed  PubMed Central  Google Scholar 

  • Kantrowitz JT, Epstein ML, Lee M et al (2018) Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res 191:70–79

    PubMed  Google Scholar 

  • Karper LP, Freeman GK, Grillon C et al (1996) Preliminary evidence of an association between sensorimotor gating and distractibility in psychosis. J Neuropsychiatr Clin Neurosci 8:60–66

    CAS  Google Scholar 

  • Kohl S, Heekeren K, Klosterkötter J, Kuhn J (2013) Prepulse inhibition in psychiatric disorders—apart from schizophrenia. J Psychiatr Res 47:445–452

    CAS  PubMed  Google Scholar 

  • Kumari V, Peters ER, Fannon D et al (2008) Uncontrollable voices and their relationship to gating deficits in schizophrenia. Schizophr Res 101:185–194

    PubMed  PubMed Central  Google Scholar 

  • Labrie V, Fukumura R, Rastogi A et al (2009) Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol Genet 18:3227–3243

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lane H-Y, Lin C-H, Green MF et al (2013) Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry 70:1267–1275

    CAS  PubMed  Google Scholar 

  • Lee S-H, Sung K, Lee K-S et al (2014) Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 48:213–219

    Google Scholar 

  • Lin C-Y, Liang S-Y, Chang Y-C et al (2017) Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial. World J Biol Psychiatry 18:357–368

    PubMed  Google Scholar 

  • Maekawa M, Takashima N, Matsumata M et al (2009) Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses. PLoS One 4:e5085

    PubMed  PubMed Central  Google Scholar 

  • Ma TM, Abazyan S, Abazyan B et al (2013) Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Mol Psychiatry 18:557–567

    CAS  PubMed  Google Scholar 

  • McGurk SR, Twamley EW, Sitzer DI et al (2007) A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry 164:1791–1802

    PubMed  PubMed Central  Google Scholar 

  • Minassian A, Feifel D, Perry W (2007) The relationship between sensorimotor gating and clinical improvement in acutely ill schizophrenia patients. Schizophr Res 89:225–231

    PubMed  Google Scholar 

  • Mishra J, de Villers-Sidani E, Merzenich M, Gazzaley A (2014) Adaptive training diminishes distractibility in aging across species. Neuron 84:1091–1103

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morita Y, Ujike H, Tanaka Y et al (2007) A genetic variant of the serine racemase gene is associated with schizophrenia. Biol Psychiatry 61:1200–1203

    CAS  PubMed  Google Scholar 

  • Panizzutti R, Fisher M, Garrett C et al (2019) Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia. Schizophr Res 207:63–69

    PubMed  Google Scholar 

  • Panizzutti R, Hamilton SP, Vinogradov S (2013) Genetic correlate of cognitive training response in schizophrenia. Neuropharmacology 64:264–267

    CAS  PubMed  Google Scholar 

  • Papouin T, Ladépêche L, Ruel J et al (2012) Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150:633–646

    CAS  PubMed  Google Scholar 

  • Paxinos G, and Franklin KBJ. (2001) The mouse brain in stereotaxic coordinates: hard cover edition. Access Online via Elsevier.

  • Robin LM, Oliveira da Cruz JF, Langlais VC et al (2018) Astroglial CB1 receptors determine synaptic D-serine availability to enable recognition memory. Neuron 98:935–944.e5

    CAS  PubMed  Google Scholar 

  • Rohleder C, Wiedermann D, Neumaier B et al (2016) The functional networks of prepulse inhibition: neuronal connectivity analysis based on FDG-PET in awake and unrestrained rats. Front Behav Neurosci 10:148

    PubMed  PubMed Central  Google Scholar 

  • Rosburg T, Kreitschmann-Andermahr I (2016) The effects of ketamine on the mismatch negativity (MMN) in humans - A meta-analysis. Clin Neurophysiol 127:1387–1394

    PubMed  Google Scholar 

  • Schell MJ, Brady RO Jr, Molliver ME, Snyder SH (1997) D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 17:1604–1615

    CAS  PubMed  PubMed Central  Google Scholar 

  • Squire LR, Genzel L, Wixted JT, Morris RG (2015) Memory consolidation. Cold Spring Harb Perspect Biol 7:a021766

    PubMed  PubMed Central  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (2016) Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol 30:1072–1081

    PubMed  PubMed Central  Google Scholar 

  • Swerdlow NR, Light GA, Sprock J et al (2014) Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. Schizophr Res 152:503–512

    PubMed  PubMed Central  Google Scholar 

  • Vargas-Lopes C, Madeira C, Kahn SA et al (2011) Protein kinase C activity regulates D-serine availability in the brain. J Neurochem 116:281–290

    CAS  PubMed  Google Scholar 

  • Vinogradov S, Fisher M, de Villers-Sidani E (2012) Cognitive training for impaired neural systems in neuropsychiatric illness. Neuropsychopharmacology 37:43–76

    PubMed  Google Scholar 

  • Voss P, Thomas ME, Guercio GD, de Villers-Sidani E (2019) Dysregulation of auditory neuroplasticity in schizophrenia. Schizophr Res 207:3–11

    PubMed  Google Scholar 

  • Wiegand A, Nieratschker V, Plewnia C (2016) Genetic modulation of transcranial direct current stimulation effects on cognition. Front Hum Neurosci 10:651

    PubMed  PubMed Central  Google Scholar 

  • Wu MF, Krueger J, Ison JR, Gerrard RL (1984) Startle reflex inhibition in the rat: its persistence after extended repetition of the inhibitory stimulus. J Exp Psychol Anim Behav Process 10:221–228

    CAS  PubMed  Google Scholar 

  • Wykes T, Huddy V, Cellard C et al (2011) A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry 168:472–485

    PubMed  Google Scholar 

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Acknowledgments

This research was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem.

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Authors and Affiliations

  1. Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Gerson D. Guercio, Yuri Anjos-Travassos, Igor Rangel, Stella Costa, André Poleto, Deborah Costa, Rafaela Chaiben & Rogério Panizzutti

  2. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Gerson D. Guercio & Etienne de Villers-Sidani

  3. Department of Psychiatry, University of Minnesota, 2312 S 6th St, Minneapolis, MN, USA

    Gerson D. Guercio

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  1. Gerson D. Guercio
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  2. Yuri Anjos-Travassos
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  3. Igor Rangel
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  4. Stella Costa
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  5. André Poleto
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  6. Deborah Costa
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  8. Etienne de Villers-Sidani
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  9. Rogério Panizzutti
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Correspondence to Gerson D. Guercio.

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Key points

• Oddball auditory training increases extracellular d-serine levels in the hippocampus.

•Mutated serine racemase impairs performance in the auditory training.

• Auditory training improves non-trained PPI responses.

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Guercio, G.D., Anjos-Travassos, Y., Rangel, I. et al. Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice. Psychopharmacology 237, 2499–2508 (2020). https://doi.org/10.1007/s00213-020-05549-1

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