Glutamate hypothesis of schizophrenia

Role of synaptic pruning

Various neurotrophic factors dysregulate in schizophrenia and other mental disorders, namely BDNF; expression of which is lowered in schizophrenia as well as in major depression and bipolar disorder. BDNF regulates in an AMPA-dependent mechanism - AMPA and BDNF alike are critical mediators of growth cone survival. NGF, another neurotrophin involved in maintenance of synaptic plasticity is similarly seen in deficit.

Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative stress on neurons; leading to inflammatory response and microglia activation. Similarly, toxoplasmosis infection in the CNS (positively correlated to schizophrenia) activates inflammatory cascades, also leading to microglia activation. The lipoxygenase-5 inhibitor minocycline has been seen to be marginally effective in halting schizophrenia progression. One of such inflammatory cascades' downstream transcriptional target, NF-κB, is observed to have altered expression in schizophrenia.

In addition, CB₂ is one of the most widely distributed glial cell-expressed receptors, downregulation of this inhibitory receptor may increase global synaptic pruning activity. While difference in expression or distribution is observed, when the CB₂ receptor is knocked out in mice, schizophreniform behaviors manifest. This may deregulate synaptic pruning processes in a tachyphlaxis mechanism wherein immediate excess CB₂ activity leads to phosphorylation of the receptor via GIRK, resultant in β-arrestin-dependent internalization and subsequent trafficking to the proteasome for degradation.

Role of endogenous antagonists

Alterations in production of endogenous NMDA antagonists such as agmatine and kynurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA receptors via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption.

AMPA receptor, the most widely distributed receptor in the brain, mediates long-term potentiation (LTP) via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions. In the regulated pathway, GluR1 dimers populate the synapse at a rate proportional to NMDA-ergic Ca2+ influx. In the constitutative pathway, GluR2/3 dimers populate the synapse at a steady state.

This forms a positive feedback loop, where a small trigger impulse degating NMDA from Mg2+ pore blockade results in calcium influx, this calcium influx then triggers trafficking of GluR1-containing(Ca2+ permeable) subunits to the PSD, such trafficking of GluR1-positive AMPA to the postsynaptic neuron allows for upmodulation of the postsynaptic neuron's calcium influx in response to presynaptic calcium influx. Robust negative feedback at NMDA from kynurenic acid, magnesium, zinc, and agmatine prevents runaway feedback.

Misregulation of this pathway would sympathetically dysregulate LTP via disruption of NMDA. Such alteration in LTP may play a role, specifically in negative symptoms of schizophrenia, in creation of more broad disruptions such as loss of brain volume; an effect of the disease which antidopaminergics actually worsen, rather than treat.

Role of a7 nicotinic

Anandamide, an endocannabinoid, is an α7 receptor antagonist. Cigarettes, consumed far out of proportion by schizophrenics, contain nornitrosonicotine; a potent a7 antagonist. This may indicate α7 pentameter excess as a causative factor, or possibly as a method of self-medication to combat antipsychotic side effects. Cannabidiol, a FAAH inhibitor, increases levels in anandamide and may have antipsychotic effect; though results are mixed here as anandamide also is a cannabinoid and as such displays some psychotomimetic effect. However, α7 nicotinic agonists have been indicated as potential treatments for schizophrenia, though evidence is somewhat contradictory there is indication a7 nAChR is somehow involved in the pathogenesis of schizophrenia.

Role of 5-HT

This deficit in activation also results in a decrease in activity of 5-HT_1A receptors in the raphe nucleus. This serves to increase global serotonin levels, as 5-HT_1A serves as an autoreceptor. The 5-HT_1B 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 could possibly be the reason antipsychotics sometimes are reported to aggravate negative symptoms as antipsychotics are 5HT₆ antagonists. This receptor being primarily GABAergic, 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 those with schizophrenia: 5-HT_2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT_2A allows a link between cortical, thus conscious, and the basal ganglia, unconscious. Axons from 5-HT_2A neurons in layer V of the cerebral cortex reach the basal ganglia, forming a feedback loop. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT_2C signalling. This feedback loop with 5-HT_2A/5-HT_2C is how the outer cortex layers can exert some control over our neuropeptides, specifically opioid peptides, oxytocin and vasopressin. This alteration in this limbic-layer V axis may create the profound change in social cognition (and sometimes cognition as a whole) that is observed in schizophrenia. However, genesis of the actual alterations is a much more complex phenomena.

Role of inhibitory transmission

The cortico-basal ganglia-thalamo-cortical 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 via the striatum. Through 5-HT_2A efferents from layer V of the cortex transmission proceeds through the striatum into the globulus pallidus internal and substantia nigra pars compacta. This core input to the basal ganglia is combined with input from the subthalamic nucleus. The only primarily dopaminergic pathway in this loop is a reciprocal connection from the substantia nigra pars reticulata to the striatum.

Dopaminergic drugs such as dopamine releasing agents and direct dopamine receptor agonists create alterations in this primarily GABAergic pathway via increased dopaminergic feedback from the substantia nigra pars compacta to the striatum. However, dopamine also modulates other cortical areas, namely the VTA; with efferents to the amygdala and locus coeruleus, likely modulating anxiety and paranoid aspects of psychotic experience. As such, the glutamate hypothesis is probably not an explanation of primary causative factors in positive symptoms, but rather might possibly be an explanation for negative symptoms.

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-HT_2A receptors 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 corticostriatal control, creates a feedback loop, resulting in abnormally strong basal ganglia output.

The root of psychosis (experiences that cannot be explained, even within their own mind) is when basal ganglia 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 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 5HT_2C receptor activity.

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. 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.

Treatment

Alterations in serine racemase indicate that the endogenous NMDA agonist D-serine may be produced abnormally in schizophrenia and that d-serine may be an effective treatment for schizophrenia.

Schizophrenia is often treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity. These medications have been seen to reduce positive symptoms, specifically persecutory delusions, and thus, researchers concluded that dopaminergic activity was linked to schizophrenic symptoms . Furthermore, dopaminergic drugs (dopamine agonists) induce hallucinations similar to those associated with schizophrenia . Dopaminergic drug abuse such as abuse of methamphetamine may result in a short lasting psychosis or provocation of a longer psychotic episode that may include symptoms of auditory hallucinations.

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. A 2006 systematic review investigated the efficacy of glutamatergic drugs as add-on:

Interestingly, though the neurological effects of antipsychotics (such as chlorpromazine hydrochloride) on brain biochemistry are almost instantaneous , schizophrenic patients treated with these drugs only see improvements in their symptoms after days to weeks .

Psychotomimetic 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). Both arylcyclohexamines have some(uM) affinity to D₂ and as triple reuptake inhibitors. PCP is representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia.

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. 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. However, Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials. This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia).

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.

Animal models

Research done on mice in early 2009 has shown that when the neuregulin-1\ErbB postsynaptic 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. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.