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.
[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.
[3][dubious – discuss] 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.
[13] Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative load on neurons; leading to inflammatory response and microglia activation.
[15] 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 b-arrestin-dependent internalization and subsequent trafficking to the proteasome for degradation.
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.
This feedback loop with 5-HT2A/5-HT2C is how the outer cortex layers can exert some control over our neuropeptides, specifically opioid peptides, oxytocin and vasopressin.
Through 5-HT2A efferents from layer V of the cortex transmission proceeds through the striatum into the globulus pallidus internal and substantia nigra pars compacta.
Dopamine hypothesis of schizophrenia elaborates upon the nature of abnormal lateral structures found in someone with a high risk for psychosis.
In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output.
[dubious – discuss] 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 (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.
[clarification needed] A 2006 systematic review investigated the efficacy of glutamatergic drugs as add-on: Ketamine and PCP were observed to produce significant similarities to schizophrenia.
[22] 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.
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.
[29] 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.
[30] 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.