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D-Serine and Schizophrenia - Joseph T. Coyle

Watching at the "D" side: D-amino acids and their significance in neurobiology
June 05 -June 09, 2016 – Lake Como School of Advanced Studies

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D-Serine and Schizophrenia - Joseph T. Coyle

  1. 1. 6/9/16 1 Lake Como School of Advanced Studies Watching at the “D” side: D-amino acids and ther significance in neurobiology 6/9/16 1 Joseph T. Coyle, MD Eben S. Draper Professor of Psychiatry and Neuroscience Harvard Medical School D-Serine and Schizophrenia
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  3. 3. Clinical  Features  of  the  Schizophrenia   Syndrome 3 • Positive Symptoms: delusions, hallucinations, thought disorder (responsive to antipsychotic drugs) • Negative Symptoms: asociality, apathy, poverty of thought, anhedonia • Cognitive Deficits: memory, executive functions, problem solving • Cognitive and negative symptoms but not positive symptoms predict disability
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  5. 5. 6/9/16 56/9/16 56/9/16 5 Impact of Schizophrenia: HUGE unmet needs Affects 1% of the population. Onset in early adulthood with lifetime disability. Seventh most costly medical illness to Society ($66 Billion/year in USA). High rates of substance abuse, homelessness and imprisonment and early death.
  6. 6. 6/9/16 6 Anti-Psychotics Drugs Have Limited Efficacy in the Treatment of Schizophrenia 1. In meta-analysis, second-generation (SG) antipsychotics (clozapine, olanzapine, risperidone) are marginally more effective than first-generation (FG) antipsychotics (Leucht et al., Lancet 373: 31, 2009). 2. 74% of patients discontinue both FG and SG antipsychotics within 18 months of treatment because of side effects or lack of efficacy (Lieberman et al., NEJM 353: 1209, 2005). 3. Antipsychotics (except clozapine) have negligible effects on cognition and negative symptoms (Essali et al., Cochrane Database Syst Rev , ePub 2009).
  7. 7. Schizophrenia has a characteristic neuropathology
  8. 8. 6/9/16 86/9/16 8 Specific Brain Structures are Shrunken in Schizophrenia 1. Atrophy of the frontal cortex, temporal cortex, hippocampus and thalamus (-3-5%) 2. Reductions in grey matter, loss of neuropil and reduction in white matter. 1. WHY? No neuronal loss in cortex. Rather, neuronal atrophy, skimpy dendrites and reduced spines, resulting in ~35% reduction in glutamatergic synapses. ControlControl Schizophrenia Glantz LA, Lewis DA. Arch Gen Psychiatry. 57:65-73, 2000. Konopaske et al., JAMA Psychiatry 71(12):1323-31, 2014.
  9. 9. 6/9/16 9 Cortical Atrophy and Schizophrenia: the (Insurmountable?) Challenge • Present at first episode. • Pervasive but affects frontal cortex and temporal cortex more severely. • Progresses for ~10 years after onset of psychosis. • Exacerbated by anti-psychotic treatment. • Correlates with negative symptoms and with cognitive impairment BUT NOT with positive symptoms
  10. 10. 6/9/16 10 GAD-67, parvalbumin-expressing, fast-firing recurrent inhibitory inter-neurons are down-regulated in schizophrenia Tamminga et al., Am J Psychiatry 161: 1764, 2004
  11. 11. 6/9/16 11 Is There Evidence of NMDA Receptor Dysfunction in Schizophrenia?
  12. 12. 6/9/16 12 Tripartite Glutamatergic Synapse JT Coyle: in Basic Neurochemistry, 2014
  13. 13. 6/9/16 13 The  NMDA  Receptor:  molecular  coincidence   detector • Depolarization Mg2+ GLU DS Ca2+ + Na+ • Agonist binding at glutamate site • Agonist binding at glycine modulatory site (GMS) Expression of synaptic genes: BDNF pathway, mTor pathway, mir132, MeCP2 Ketamine
  14. 14. Blakely RD, Robinson MB, Thompson RC, Coyle JT.Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate: subcellular and regional distribution, ontogeny, and the effect of lesions on N-acetylated-alpha-linked acidic dipeptidase activity. J Neurochem. 1988 Apr;50(4):1200-9. Rhesus cortex NAAG-IC a, b, GCPII in situ; c, double label; d, GFAP; e, control
  15. 15. 6/9/16 15 Arch Gen Psychiatry 52: 829-36, 1995. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT. “RESULTS: Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in Glutamate Carboxypeptidase2 (GCP2) activity. Levels of NAAG (an NMDA receptor antagonist) were increased and GCP2 activity and glutamate levels were decreased in the schizophrenic brains…. CONCLUSIONS: These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems….”
  16. 16. 6/9/16 16 Rowland et al., Schizophr Bull 39: 1096-1104, 2013 The levels of N-acetyl aspartyl glutamate in forebrain significantly correllate with negative symptoms in schizophrenia in vivo shown by MRS
  17. 17. 176/9/16 17 NMDA Receptor Hypofunction and Schizophrenia • Ketamine infusion in normal volunteers: Replicates positive, negative and cognitive symptoms Replicates physiologic signs: hypofrontality, elevated subcortical dopamine release, eye tracking, disrupted gamma rhythms. • Endogenous NMDA GMS antagonists are elevated in brain and CSF: kynurenic acid, N-acetylaspartyl- glutamate (act at the glycine modulatory site). • D-serine levels are reduced in CSF and serum • Schizophrenia-like symptoms in early stages of NMDA receptor auto-immune disorder: Brain On Fire
  18. 18. 6/9/16 18 SR-/- Mice as a Genetically Valid Model of Cortical Pathology in Schizophrenia
  19. 19. 6/9/16 19 Basu et al., Mol Psychiatry 14: 19-27, 2009 Serine Racemase (SR) Null Mutation Prevents SR Expression in Brain Cortical D-Serine <15% of WT NMDA receptor function is decreased by >70%
  20. 20. 6/9/16 206/9/16 20 Acute Hippocampal Slice Preparation Shows Impaired Long-Term Potentiation in SR-/- Mice Basu et al., Mol Psychiatry 14:719-27, 2009 DeVito et al., Genes Brain Behav. 10:210-22, 2011 Balu et al., PNAS USA 110:E2400-9, 2013
  21. 21. 6/9/16 216/9/16 216/9/16 21 SR-/- Mice Exhibit Cognitive Impairments in Several Domains Cognitive Impairments: Probe task in Morris water maze, sequential memory, contextual fear conditioning Basu et al., Mol Psychiatry 14:719-27, 2009 DeVito et al., Genes Brain Behav. 10:210-22, 2011 Balu et al., PNAS USA 110:E2400-9, 2013 MWM Probe Trial
  22. 22. 6/9/16 22 SR-/- mice primary sensory pyramidal neurons have less complex dendritic structure and fewer spines D Balu, A Basu and JT Coyle, Neurobiol Dis 45: 671-82, 2012 Cortical volume: -3.5%, P<0.05 ~35% Reduction in glutamatergic synapses
  23. 23. Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):E2400-9. 23 Schizophrenia and SR-/- mice have reduced BDNF/TrkB signaling
  24. 24. 6/9/16 24 Akt/mTOR signaling are reduced in schizophrenia and SR-/- mice Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):E2400-9.
  25. 25. 6/9/16 25 miRNA 132 is reduced in schizophrenia and in SR-/-
  26. 26. Balu DT and Coyle JT. Neurosci Letts 517: 77-81, 2012. Silencing SR expression in cortical pyramidal neurons in young adulthood (CamKIICre2834) partially impairs dendrite and spine formation on S1 pyramidal neurons
  27. 27. SR-/- results in increased oxidative stress and decreased parvalbumin staining GABAergic neurons in the anterior cingulate cortex Do et al., in preparation WPA is a marker for the perineural net
  28. 28. SR-/- Mice Exhibit Anhedonia as Demonstrated in Intracranial Self Stimulation Carlezon WA Jr, Chartoff EH. Nat Protoc. 2007;2(11):2987-95; Puhl M, in preparation,
  29. 29. 6/9/16 29 SR-­/-­ NMDA  Receptor  Hypofunction Schizophrenia  Endophenotype Replicates   Forebrain  MRS  Glutamate  and  GABA  Findings Puhl et al., Neurobiology of Disease, 73C: 269-74, 2014. Schizophrenia: elevated MRS GABA: Kegeles et al., 2012; dela Fuente-Sndoval; elevated MRS Glutamate: Kegeles et al., 2012; Ongur et al., 2010.
  30. 30. 6/9/16 306/9/16 306/9/16 30 Similarities between SR-/- mice and schizophrenia cortical pathology 1. Cortical atrophy ✔ ✔ 1. Reduced dendritic complexity ✔ ✔ 2. Reduced spines ✔ ✔ 3. Reduced neuroplastic pathway function BDNF, Akt, mTor ✔ ✔ 5. Oxidative stress, PV/GABA ✔ ✔ 6. Cognitive impairments ✔ ✔ 7. Anhedonia (Negative symptoms) ✔ ✔ Schiz SR-/- DeVito et al., Genes Brain Behav. 10:210-22, 2011; Balu et al. , Neurobiology of Disease, 45: 671-82, 2012; Basu et al., Mol Psychiatry. 14:719-27, 2009; Balu et al., Proc Natl Acad Sci USA, 2013.
  31. 31. 6/9/16 316/9/16 316/9/16 316/9/16 31 Serine Racemase is expressed in pyramidal and in GABAergic inter-neurons but not in astrocytes in human cortex Balu et al., Cell Mol Neurobiol 34: 419, 2014
  32. 32. D-Serine does not co-localize with astrocytic markers in cortex Balu DT, Takagi S, Puhl MD, Benneyworth MA and Coyle, JT. Cell Mol Neurobiol 34: 419-435, 2014.
  33. 33. 6/9/16 33 Does enhancing NMDA Receptor Function Affect the Symptoms of Schizophrenia?
  34. 34. 6/9/16 34 Goff et al., Am J Psych 152: 1213, 1995 Dose Finding Study for D-Cycloserine in Schizophrenia
  35. 35. 6/9/16 356/9/16 35 GlyT1 inhibitor, NFPS, demonstrates that the glycine modulatory site on synaptic NMDA receptors is not fully occupied by glycine/D-serine Bergeron et al., Proc Natl Acad Sci U S A. 95:15730-4, 1998.
  36. 36. 6/9/16 366/9/16 36 M D-Cycloserine Treatment for 8 Weeks versus Placebo: fMRI of a Memory Task Yergulin-Todd et al., Psychiat Res (Neuroimaging) 138 (2005): 23-31.
  37. 37. 6/9/16 37 M D-Cycloserine Treatment for 8 Weeks versus Placebo Improves Memory: fMRI of a Memory Task Yergulin-Todd et al., Psychiat Res (Neuroimaging) 138 (2005): 23-31.
  38. 38. 6/9/16 38 M D-Cycloserine Treatment for 8 Weeks improves memory, increases cortical blood flow and reduces negative symptoms in schizophrenia Right Superior Temporal Gyrus 0.82 +/- 0.58 Left Superior Temporal Gyrus 1.88 +/- 0.34* Temporal Lobe Activation and Negative Symptoms (PANSS) r= -0.77* +/- S.D. * p< 0.05 Yergulin-Todd et al., Psychiat Res (Neuroimaging) 138 (2005) :23-31.
  39. 39. Tsai et al., 1998 (N=29) Heresco-Leveyet al., 2005 (N=38) BPRS/CGI -2.2** -5.7** SANS -10.4** -7.9** PANSS-Cog -1.7* -1.3** PANSS-Pos -3.4** -1.4* 6/9/16 *p < 0.05; **p < 0.01 Addition of D-Serine (2g/day) to Anti-Psychotic Drugs Reduces All Symptoms in Patients with Chronic Schizophrenia
  40. 40. 6/9/16 40 Meta-analysis of Placebo-Controlled Glycine Modulatory Site Agonist Clinical Trials in Schizophrenia “About eight hundred subjects from 26 studies were included in current meta-analysis. Overall, the NMDA-enhancing molecules are effective in most schizophrenic symptom domains with the effect size (ES) of total psychopathology of 0.40 (p<1x10-4). The ES of clinical efficacy of the symptom domains were in the order of depressive (0.40, p=3x10-4), negative (0.38, p<1x10-4), cognitive (0.28, p=2x10-3), positive symptom (0.26, p=0.0006), and general psychopathology (0.26, p=0.006).” Proof of concept but limitations as treatments….. Tsai GE, Lin PY. Current Pharmaceutical Design 16: 522-37, 2010
  41. 41. 6/9/16 41 Is It Possible to Reverse the Neuroplasticity Deficits in SR-/- Mice?
  42. 42. 6/9/16 42 3 Weeks of D-Serine Treatment Restores D-Serine Levels in Brain in SR-/- Mice Balu et al., PNAS USA 2013 Jun 25;110(26):E2400-9.
  43. 43. 6/9/16 43 Chronic D-Serine Reverses LTP, Spine Deficits and Trophic Pathway Reductions in SR-/- Mice Balu et al., PNAS USA 2013 Jun 25;110(26):E2400-9. Balu and Coyle. Neurochem Intern. 75: 76-78, 2014. P-TrkB, P-Akt, P-mTOR levels are restored by D-serine.
  44. 44. 6/9/16 446/9/16 44 Chronic Systemic D-Serine Treatment Reverses Memory Deficits (Hippocampal) in SR-/- Mice Balu et al., Proc Natl Acad Sci USA, 2013.
  45. 45. 6/9/16 45 Genetic Studies Independently Confirm Glutamatergic Hypothesis of Schizophrenia
  46. 46. 6/9/16 466/9/16 46 Copy Number Variants (CNVs) and the Risk for Schizophrenia In an analysis of 18,492 subjects (7907 cases and 10585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015)…Our data indicate that defects in NMDAR postsynaptic signaling…which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia. Kirov et al., Mol Psychiatry 17: 142-­53, 2012.
  47. 47. 6/9/16 47 Study Genome-­Wide  Association  Study  (GWAS)   of  113,075  controls  and  36,989   schizophrenic  subjects  reveal  108  risk  loci. Ripke et  al.,  Nature 511:  421,  2014.   Serine Racemase 17q13
  48. 48. 6/9/16 48Coyle JT and Balu DT. Current Opinion Pharmacol 20: 109-115, 2015. Multiple  Schizophrenia  Risk  Genes  Converge   on  NMDA  Receptor  Signaling mGluR3' Glu' Astrocyte GRIN2A Risk'Genes' GRM3 GRIA1 DLG1 DLG2 CLCN3 SRR AKT3 CO2 0' H' NH3 +' OH' L"serine( CO2 0' NH3 +' H' OH' D"serine( SR' Pre"synap.c( MEF( Nucleus( PSD Akt3( SAP97' DS'Glu' NR2A' mGluR3' Glu' PSD93' Cl- ClC-3 Glu' SAP97' PSD93' GluR1' D-serine Glutamate Transcription factor/repressor MEF2
  49. 49. Genetic models are useful for identifying treatments that address the pathophysiology of schizophrenia.
  50. 50. 5 Day Treatment with a mGluR5 Positive Allosteric Modulator (VU-551) Reverses Neuroplasticity Deficits in SR-/- Mice Balu DT, Li Y, Takagi S, Presti KT, Ramikie TS, Rook JM, Jones CK, Lindsley CW, Conn PJ, Bolshakov VY, Coyle JT. Neuropsychopharmacology. 2016 Jan 7. doi: 10.1038/npp.2016.2.
  51. 51. Balu DT, Li Y, Takagi S, Presti KT, Ramikie TS, Rook JM, Jones CK, Lindsley CW, Conn PJ, Bolshakov VY, Coyle JT. Neuropsychopharmacology. 2016 Jan 7. doi: 10.1038/npp.2016.2. VU-551, a mGluR5 positive allosteric modulator, restores CA3-CA1 LTP and contextual fear conditioning
  52. 52. Complement C4 Gene Major Histocompatability Complex Risk Locus for Schizophrenia (HSA 6) Encodes Complement C4 “Each common CA4 allele associating with schizophrenia (was) in proportion to its tendency to generate greater expression of C4A. In mice, C4 mediated synapse elimination during post-natal development. The results…may help explain the reduced number of synapses in the brains of individuals with schizophrenia.” Sekar A et al.,Schizophrenia risk from complex variation of complement component 4. Nature. 2016 Feb 11;530(7589):177-83.
  53. 53. 6/9/16 53 Schizophrenia  is  a  circuit   disorder  offering  many  targets   for  potential  pharmacologic     interventions
  54. 54. 6/9/16 54 DA Glu Glu GABA Ventral Striatum Psychosis Disinhibition Cognitive Impairment NMDA Receptor Hypofunction + + VTA NBM ↓Alpha 7 nAChR + Dendritic dysplasia Ketamine NAAG/Kynurenate mGluR3, Arc, NRG1, GRIK3, GRIN2A, SR
  55. 55. Summary • Many risk genes for schizophrenia including serine racemase and C4A regulate synaptic plasticity and are associated with reduced cortical glutamatergic synapses (~-30%). • Knocking out SR replicates many of the pathologic features of schizophrenia including reduced synaptic connectivity, cortical atrophy, reduced PV+GABAergic staining, negative symptoms and cognitive impairments (genetic model with construct validity) • SR and D-serine are localized to forebrain glutamatergic and PV+GABAergic neurons where D-serine serves as the synaptic co-agonist at NMDA receptors • Much of the SR-/- phenotype can be reversed by treating adult SR-/- mice with D-serine or an mGluR5 PAM, holding out hope for pharmacologic reversal of the glutamatergic disconnection in schizophrenia and effective treatment of cognitive and negative symptoms
  56. 56. Conclusions 1. Impairments in pathways mediating synaptic plasticity are a common pathophysiologic feature of serious mental disorders 2. Glutamatergic neurotransmission is a critical mediator 3. Regions of impairments dictate symptoms: widespread in cortex in schizophrenia; hippocampus, prefrontal cortex in mood disorder; nucleus accumbens and prefrontal cortex in addictions; striatum in obsessive compulsive disorder 4. Restorative treatments likely require enhancement of pro- neuroplastic pathways AND targeted neurocognitive interventions