Glutamate hypothesis of schizophrenia

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models.[1] The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.[2]

Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.

GPCRs and Schizophrenia

We know that hypofunctioning glutamate receptors are a contributing factor in developing schizophrenia (Mechri, A 2001). Alterations in the expression, distribution, autoregulation,(Catapano, L Manji, H, 2006) prevalence of specific heterodimers,(Gonzales, 2012) and relative levels of G proteins, specifically lowered levels of the i isomorph,(F Odaka, T.J Crow, G.W Roberts) all can result in an altered NMDA function. The primary contributor to schizophrenia is a relative deficit of presynaptic glutamate receptors to the postsynaptic receptors. Specifically, group II is indicated in this disorder, given that mGlu2/3 agonists have been found useful in the treatment of both positive and negative symptoms. However, all regulatory neurotransmitters are involved, as every metabotropic receptor has potential to alter glutamatergic function.(Sugai, 2006) Specifically, 5-HT has an extraordinarily wide role in modulatory processes of the brain, as such, it is highly implicated in all CNS function. In addition, CB1 plays a global inhibitory role, serving to inhibit the release of all neurotransmitters. In addition, CB1 is one of the most widely distributed receptors in the brain, thus, downregulation of this receptor will increase global chemical synaptic activity. No difference in expression or distribution is observed, but when the CB1 receptor develops a tolerance, 2-AG(full) cannot exert its full inhibitory effects on GABA and glutamate release. A deficit in endocannobinoid metabolism, or excess catabolism, as well as heavy cannabis use, will deregulate global chemical transmission.

This is the key in schizophrenia: the fact that this deregulates glutamate carboxylase expression, which acts to downregulate reelin production, the crucial mediator of neurogenesis. Specifically, the reelin expressing Cajal-Retzius cells are of interest. These cells are a crucial component of corticocortical transmission, due to their long, nearly horizontal axons, multiple synapses, and consistent termination on spiny pyramidal neurons. These allow for interlayer communication over a wider area than those without, e.g. chimpanzees. This is the part of the neurological system which is most different, and the part of the genome which is most "accelerated" vs chimpanzees. This would indicate that this is a necessary factor for the development of the so-called speech centers of the brain, Wernickie's and Broca's areas. Also, a deficit in reelin activity is associated with cortical developmental retardation. These neurons also express 5-HT3 significantly, which is the only serotonergic ligand gated ion channel. Presynaptically, they act to regulate neurotransmitter release, mediating the frequency and strength of tonic firing in connected neurons. This is likely the mechanism through which they mediate long term potentiation. A deficit in this activity would alter plasticity significantly, contributing to the illnesses of bipolar disorder and schizophrenia.

5-HT

This deficit in activation also results in a decrease in activity of 5-HT1A receptors in the raphe nucleus.(Bantick, Deakin, Grasby 2001) This serves to increase global serotonin levels, as 5-HT1A serves as an autoreceptor. The 5-HT1B receptor, also acting as an autoreceptor, specifically within the striatum, but also parts of basal ganglia then will inhibit serotonin release. This disinhibits frontal dopamine release. The local deficit of 5-HT within the striatum, basal ganglia, and prefrontal cortex causes a deficit of excitatory 5-HT6 signalling. This receptor is primarily GABAergic, as such, it causes an excess of glutamatergic, noradrenergic, dopaminergic, and cholinergic activity within the prefrontal cortex and the striatum. An excess of 5-HT7 signaling within the thalamus also creates too much excitatory transmission to the prefrontal cortex. Combined with another critical abnormality observed in schizoid patients: 5-HT2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT2A allows a link between cortical, thus conscious, and the basal ganglia, unconscious. Axons from 5-HT2A neurons in layer V of the cerebral cortex reach the basal ganglia, forming a feedback loop, allowing us to condition ourselves. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT2C signalling. This feedback loop with 5-HT2C is how the outer cortex layers can exert some control over our neurochemicals, specifically oxytocin and vasopressin. This alteration in this limbic-layer five axis creates the profound change in social cognition, and sometimes cognition as a whole that is observed in schizoid patients. However, genesis of the actual alterations is a much more complex phenomena.

The role of inhibitory transmission

The cortico-striatal-thalamic loop, is the source of the ordered input necessary for a higher level upper cortical loop. Feedback is controlled by the inhibitory potential of the cortices. Through 5-HT2A efferents from layer V, transmission, processed, from layer III through the interneuron layer reaches the basal ganglia and brain stem. The core thalamic input to layer I is combined with the ordered matrix input to VI. A process happens with layer III/I and II/III efferents: these circuits are where our self/other perception, and the mechanisms for logic lie.(anteriorly) Also, it is how, through the entorhinal cortex, which almost completely lacks layer IV, can control orbitofrontal and thalamic output from the hippocampus, as well as (indirectly) provide a pathway for hippocampal communication to the other cortices. This is opposed by the frontal lobes, which have much larger granular areas, thus inhibitory potential,from input to the striatum.

Another modulatory factor is the corpus callosum, providing a direct inhibitory connection, interhemispherical, to the cortical layer VI, thus indirectly to layer V. As such, the halves of the brain exert some control over basal input of the other side, but can only inhibit due to the GABAergic nature of the corpus callosum. The root of this control is an extraordinarily complex dihemispherical beat frequency in layer IV between layer V and layers II/III. One might say qualia happens here. How the other side can (indirectly) inhibit the 5-HT2A signal cascade, is crucial for the development of language. It requires highly structured left side structures allowing for the imagination of the formants, and the mouth movements that correspond to them. It also needs a more distributed, contextual, reality based side, to integrate the naturally nonsensical medium of language back to intuitive sensory/spatial analogies.

Dopamine hypothesis of schizophrenia elaborates upon the nature of abnormal lateral structures found in someone with a high risk for psychosis.

Altered signalling cascades

Again, thalamic input from layer V is a crucial factor in the functionality of the human brain. It allows the two sides to receive similar inputs, thus be able to perceive the same world. In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output. This is due to excessive D2 and 5-HT2A activity. This alteration in input to the top and bottom of the cortex. The altered 5-HT signal cascade enhances the strength of excitatory thalamic input from layer V. This abnormality, enhancing the thalamic-cortical transmission cascade versus the corticostriratal control, creates a feedback loop, resulting in abnormally strong basal ganglic output.

The root of psychosis(experiences that cannot be explained, even within their own mind) is when basal ganglic input to layer V overwhelms the inhibitory potential of the higher cortexies resulting from striatal transmission. When combined with the excess prefrontal, specifically orbitofrontal transmission, from the hippocampus, this creates a brain prone to falling into self reinforcing belief.

However, given a specific environment, a person with this kind of brain(a human) can create a self-reinforcing pattern of maladaptive behavior, from the altered the layer II/III and III/I axises, from the disinhibited thalamic output. Rationality is impaired, primarily as response to the deficit of oxytocin and excess of vasopressin from the abnormal 5HT2C activity. An altered HPA axis, perhaps from xenohormones, drug use, or a genetic predisposition to altered adregenic and norepineprine signalling. An altered HPA axis, in the direction of more activation and stress, is the primary pathological trait in all social disorders.

Frontal cortex activity will be impaired, when combined with excess DA activity: the basis for the advancement of schizophrenia, but it is also the neurologic mechanism behind many other psychotic diseases as well. Only with a specific psychosocial perception of the world will a patient with a high risk of psychosis develop it. Heredity of schizophrenia may even be a result of specific parenting techniques passed on though generations, and not just genetics. However, the genetic component is the primary source of the neurological abnormalities which leave one prone to psychological disorders. Specifically, there is much overlap between bipolar disorder and schizophrenia, and other psychotic disorders. They all are linked to prenatal trauma, excessive drug use, specifically dissociatives, psychedelics, stimulants, and marijuana, as well as abnormalities in receptor expression.

Current state of schizophrenia treatment

Schizophrenia is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms, specifically persecutory delusions. Dopaminergic drugs do not induce the characteristic auditory hallucinations of schizophrenia. The typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, do not significantly reduce negative symptoms.

Glutamate antagonists

Ketamine and PCP were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). PCP however is less representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia.[3] Although unconfirmed, Dizocilpine discovered by a team at Merck seems to model both the positive and negative effects in a manner very similar to schizophreniform disorders.

Possible glutamate based treatment

An early clinical trial by Eli Lilly of the drug LY2140023 has shown potential for treating schizophrenia without the weight gain and other side-effects associated with conventional anti-psychotics.[4][5][6] A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response.[7] However, Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials.[8][9] This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).[10]

Studies of glycine (and related co-agonists at the NMDA receptor) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.[11]

Animal models

Research done on mice in early 2009 has shown that when the neuregulin-1\ErbB post-synaptic receptor genes are deleted, the dendritic spines of glutamate neurons initially grow, but break down during later development. This led to symptoms (such as disturbed social function, inability to adapt to predictable future stressors) that overlap with schizophrenia.[12][13] This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.

See also

Notes and references

  1. ↑ Lisman JE, Coyle JT, Green RW, et al. (May 2008). "Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia". Trends in Neurosciences. 31 (5): 234–42. doi:10.1016/j.tins.2008.02.005. PMC 2680493Freely accessible. PMID 18395805.
  2. ↑ Behrens MM, Ali SS, Dao DN, et al. (December 2007). "Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase". Science. 318 (5856): 1645–7. doi:10.1126/science.1148045. PMID 18063801.
  3. ↑ Reynolds LM, Cochran SM, Morris BJ, Pratt JA, Reynolds GP (March 2005). "Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain". Schizophrenia Research. 73 (2–3): 147–52. doi:10.1016/j.schres.2004.02.003. PMID 15653257.
  4. ↑ Patil ST, Zhang L, Martenyi F, et al. (September 2007). "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial". Nature Medicine. 13 (9): 1102–7. doi:10.1038/nm1632. PMID 17767166.
  5. ↑ Berenson, Alex (2008-02-24). "Daring to Think Differently About Schizophrenia". The New York Times. Retrieved 2010-05-03.
  6. ↑ "Schizophrenia trials 'promising'". BBC News. 2007-09-02. Retrieved 2010-05-03.
  7. ↑ Eli Lilly and Company - Lilly Announces Inconclusive Phase II Study Results for mGlu2/3 at the International Congress on Schizophrenia Research, Eli Lilly, 29 March 2009
  8. ↑ Strike three: Bad data bury Eli Lilly's late-stage schizophrenia drug
  9. ↑ LY2140023 – Treatment of Schizophrenia
  10. ↑ Harrison PJ, Weinberger DR (January 2005). "Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence". Molecular Psychiatry. 10 (1): 40–68; image 5. doi:10.1038/sj.mp.4001558. PMID 15263907.
  11. ↑ Tuominen HJ, Tiihonen J, Wahlbeck K (2006). Wahlbeck, Kristian, ed. "Glutamatergic drugs for schizophrenia". Cochrane Database of Systematic Reviews (2): CD003730. doi:10.1002/14651858.CD003730.pub2. PMID 16625590.
  12. ↑ "How Microscopic Changes To Brain Cause Schizophrenic Behavior In Mice".
  13. ↑ Barros CS, Calabrese B, Chamero P, et al. (March 2009). "Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system". Proceedings of the National Academy of Sciences of the United States of America. 106 (11): 4507–12. doi:10.1073/pnas.0900355106. PMC 2657442Freely accessible. PMID 19240213.

Further reading

External links

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