Schizo- glutamate

1. Glutamate hyperactivity

   Annotations:

   • rather than hypoactivity Possibly via AMPAR
   1. Animal studies
      1. Moghaddam et al, 1997

         Annotations:

         • awake animals (but not in brain slice preparations or anesthetized animals), systemic injection of NMDAR antagonists at doses that impaired cognitive functions and produced motor stereotypy increase glutamate efflux in the prefrontal cortex
         • This increase in the extracellular levels of glutamate had functional significance because blockade of AMPA receptors reduced the motoric and cognitive detriments of NMDAR blockade
         1. NMDAR anta- impaired cognitive
         2. AMPAR blockage- reversed it
         3. NMDAR anta- increase Glu
            1. acts of AMPAR
      2. Jackson et al, 2004

         Annotations:

         • single unit recordings in awake rodents measuring random spiking of spontaneously active neurons 
   2. NMDAR deficiency

      Annotations:

      • NMDAR deficiency is not due to a generalized ‘glutamate hypofunction’ but dysregulation of glutamate neurotransmission that may potentially involve NMDAR hypofunction but excessive activity of non-NMDA receptors.

      Attachments:

      • Schizophrenia
      1. GABA

         Annotations:

         • what is the mechanism by which an NMDAR antagonist increases and thus disorganizes the firing of cortical neurons? 

         Attachments:

         • Schizophrenia
         1. cortical disinhibition
         2. have NMDAR
         3. NMDAR anta>> inhibit GABA neurons

            Annotations:

            • NMDAR antagonist produces a transient decrease in firing rate of GABA neurons that in turn enhances the firing of pyramidal neurons (Homayoun and Moghaddam, 2007b). 
            1. Homayoun and Moghaddam, 2007

               Annotations:

               • Awake rats- inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons 
   3. humans
      1. fMRI

         Annotations:

         • neuronal activity in the PFC was generally enhanced by NMDAR antagonists in human fMRI studies measuring metabolic activation in PFC regions
      3. Glu 2/3 receptor agonists

         Annotations:

         • reducing the release of glutamate by metabotropic glutamate group 2/3 receptor agonists also reduced the behavioral and cellular effects of NMDAR antagonists
         • localized extrasynaptically including on presynaptic terminals. Activation of these receptors by exogenous agonists reduces activated release of glutamate
         1. Rodent studies

            Annotations:

            • Rodent studies showed that these exogenous agonists reduced NMDAR antagonist-activated release of glutamate and cortical hyperactivity at the same time they ameliorated the aberrant behavioral effects of these antagonists, including PCP and MK801
            1. Moghaddam and Adams, 1998
         2. Human
            1. Krystal et al, 2005

               Annotations:

               • healthy volunteers showed that mGlu2/3 receptor agonists also reduced some of the cognitive impairing effects of ketamine in healthy volunteers
         3. Clinical trials
            1. Patil et al (2007)

               Annotations:

               • demonstrated comparable efficacy between an mGlu2/3 receptor agonist and the atypical antipsychotic drug olanzopine for treating negative and positive symptoms (Patil et al, 2007) without the metabolic and motor-related side effects generally associated with antipsychotic drug
            2. Kinon et al, 2011

               Annotations:

               • inclusive because both the mGlu2/3 agonist and olanzopine did not significantly separate from placebo
         4. NMDAR deficiency

Attachments:

• Schizophrenia

1. Glycine
   1. synthesis

      Annotations:

      • Glycine in brain is synthesized primarily from l-serine by serine hydroxymethyltransferase, and regulated synaptically by glycine (GlyT1) transporters
   2. limited evidence in Schizo
      1. GlyT1 transporters

         Annotations:

         • may be an appropriate target for therapeutic intervention, potentially raising synaptic glycine to super-physiological levels in order to compensate for disturbances elsewhere in the system
         1. Javitt, 2009
         2. blockage of it

            Annotations:

            • clinical trials currently undegoing
2. D-serine
   1. synthesis

      Annotations:

      • d-serine is synthesized in brain from l-serine by serine racemase, and degraded by d-amino-acid oxidase, which, in turn, is modulated by the protein G72.
   2. Genetic studies

      Annotations:

      • associations of both enzymes with schizophrenia
   3. knockouts

      Annotations:

      • serine racemase knockout mice show behavioral and structural abnormalities similar to those observed in schizophrenia, with a phenotype that can be rescued by crossbreeding with d-amino-acid oxidase (DAAO) knockouts
      1. similar behavioural abnormalities to schizo
   4. reduction is D-serine
   5. Review- Labrie and Roder, 2009

      Annotations:

      • reductions in d-serine levels have been demonstrated in both plasma and CSF in schizophrenia, suggesting potential physiological relevance to the genetic abnormalities
3. Glutathione
   1. impairment linked to Schizo
   2. MRS and CSF measurements

      Annotations:

      • magnetic resonance >>reduced glutathione levels have been demonstrated in schizophrenia
   3. enzymes

      Annotations:

      • associations also have been reported for several of the glutathione synthetic enzymes
      1. Rodriguez-Santiago et al, 2010
4. Clozapine

   Annotations:

   • effectively reduces the impact of NMDA receptor antagonists on cortical neuron hyperactivity (Homayoun and Moghaddam, 2007a). Among its many pharmacological effects, clozapine significantly potentiates NMDAR transmission in the brain, by inhibition of system A-type glycine transporters in the brain (Javitt et al, 2004). Similarly, clozapine, along with d-serine and GlyT1 inhibitors, block PCP effects on social recognition (Shimazaki et al, 2010) and other rodent models

1. 1. Observation- ketamine and PCP

   Annotations:

   • anesthestics phencyclidine (PCP) and ketamine induced negative symptoms and cognitive dysfunction similar to that of schizophrenia
   1. work by blocking NMDAR
2. 2. Glutamate receptor anta

   Annotations:

   • antagonists at both the glutamate binding site (eg CGS-19755) and the glycine modulatory site (eg, CP-101,606) also induce psychotomimetic effects when administered clinically
   1. Preskorn et al, 2008

      Annotations:

      • randomized, placebo-controlled, double-blind study >> used NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606 >> found to have antidepressant effects
3. 3. Autoimmune

   Annotations:

   • Finally, it has been observed recently that psychosis related to systemic lupus erythematous and other autoimmune disorders may be due to the production of CNS-penetrant anti-NMDAR antibodies
   1. Omdal et al (2005)

      Annotations:

      • Study in patients with systemic lupus erythematosus (SLE)   using NMDAR anti-NR2 antibodies >>elevated levels of anti-NR2 antibodies were associated with psychosis- including schizophrenia behaviours
4. vs DA hypothesis
   1. Brain region targets
      1. prefrontal/ striatum in DA

         Annotations:

         • symptoms are seen as arising from dysfunction within a limited number of brain regions, such as dorsolateral prefrontal cortex (Lesh et al, 2011) or striatum (Simpson et al, 2010), 
      2. cortical /subcortical regions- Glutamate
5. Glutamate hypothesis
   1. NMDAR hypofunction

      Annotations:

      • leads to expression of schizophrenia symptoms >>two broad classes of questions with regard to NMDAR dysfunction remain unanswered. First, what causes NMDAR dysfunction on an etiological level and second, what approaches may be most effective in reversing underlying abnormalities
      1. Q1- what causes abnormalities
      2. Q2- How to reverse them

Annotations:

• A sustained activation of receptors that mediate glutamate neurotransmission could result in neurotoxicity or adaptive responses that may be detrimental to cortical function. Thus, a more practical approach is to modulate the function of these receptors in an activity-dependent manner, ie, to enhance or reduce their function transiently in response to an incoming stimulus. This function is served naturally in the brain by the so-called allosteric modulatory sites on many brain receptors. These sites, when activated, enhance the function of the natural neurotransmitters in stimulating the targeted receptor. In other words, they only work to modulate the function of the receptor when the receptor is stimulated by the natural neurotransmitter.

1. Intrinsic sites

   Annotations:

   • Overall, significant effects have been observed in several single-site studies of both glycine and d-serine However, multicenter studies showed substantial placebo affect>> it cannot be determined whether these should be interpreted as negative or failed studies
   1. glycine sites
      1. glycine transport inhibitors
         1. animal models
            1. Javitt (2009)

               Annotations:

               • high-affinity glycine transport inhibitors have been developed and shown to be effective in multiple animal models related to schizophrenia
            2. Possibility of toxicity

               Annotations:

               • Although initial high-affinity compounds, such as NFPS, showed unexpected toxicity such as compulsive walking (‘obstinate progression’) and respiratory distress in initial in vivo animal studies, these side effects were subsequently shown not to be NMDAR mediated
         2. Clinical studies
            1. high-affinity GlyT1 compound
               1. Umbricht et al, 2010

                  Annotations:

                  • high-affinity GlyT1 compound, RG-1678 (Roche), was studied in a phase II program involving 323 subjects
                  • inhibition of GlyT1-mediated transport does indeed lead to increased CNS glycine levels, and second, that resultant allosteric NMDAR via the glycine modulatory site may be therapeutically beneficial
                  1. therapuetically beneficial
   2. D-serine
      1. DAAO inhibition

         Annotations:

         • prevent renal and brain d-serine degradation
         1. animal models
            1. Hashimoto et al, 2009

               Annotations:

               • 30-fold increase in d-serine potency in animal models , potentially decreasing clinically effective doses of d-serine from gram to milligram levels
            2. knock out of renal DAAO

               Annotations:

               • prevents d-serine toxicity
               1. Konno et al, 2010
         2. still in preclinical stage
2. Extrinsic sites

   Annotations:

   • enhance NMDAR is by targeting metabotropic glutamate receptors, which, in turn, may modulate either glutamate presynaptically or NMDAR postsynaptically
   1. mGluR5

      Annotations:

      • localized near NMDARs, modulate the dynamics of NMDAR channels by increasing NMDAR-mediated current
      1. indirect modulation of NMDAR
      2. preclinical- mGluR5 agonists

         Annotations:

         • shown to be effective in specific preclinical models of schizophrenia, although issues related to regional expression and potential downregulation during chronic treatment need to be resolved
   2. mGluR2/3 agonsits
   3. AMPA-type glutamate receptors