|A picture drawn by a Schizophrenic patient illustrating his hallucination.
He hallucinated about being wheeled past a scene of mass execution and
described hearing the cries and groans of the people who were being beheaded.
Schizophrenia is a debilitating and complex mental disorder that affects a huge number of people around the world. Although the term schizophrenia was coined decades ago, with the first antipsychotic drugs discovered in the 1950s and its effect on monoamine receptors in the 1960s , mechanisms underlying the disorder is still relatively unknown. Genetic studies have established that the disorder has high heritability, increasing susceptibility to the illness but is not solely responsible for its development in a person. Other triggers and environmental factors such as pregnancy and birth complications, drug abuse, improper child development, etc., also play a role. This has led to the understanding that the disorder is dynamic and involves the dysregulation of multiple pathways, which includes abnormalities in several neurotransmitter systems and signal transduction pathways. However, it remains unknown whether these abnormalities are causal in nature or not.
In an attempt to understand the cellular and molecular mechanisms of the disorder, researchers have postulated a number of hypotheses. These hypotheses not only attempt to account for the symptoms but also attempt to provide potential therapeutic strategies in order to reduce its severe prognosis.
Schizophrenia shares co-morbidity with numerous disorder which include anxiety disorders, depression, substance abuse, etc. These disorders also show neurotransmitter dysfunctions. There are many other mental disorders such as Autism (see Autism), Bipolar Disorder (see Bipolar Neuroscience), and Parkinson's disease (see Parkinson's Disease) that have also shown abnormal neurotransmission.
|Neurotransmitters in the Brain|
|Figure 1: In vitro densities of D2 receptors in
Schizophrenic individuals. There is an approx. 50% increase
in the density compared to control (Seeman, 1987)
|Schizophrenia and Dopamine|
A number of hypotheses attempt to explain the neurochemical aspect of the illness, of which, the oldest and most well-established of them is the Dopamine Hypothesis.
Dopamine is known to play an important role in psychosis, emotional disturbances, cognitive impairment as well as movement disorders. The Dopamine hypothesis was originally proposed by Van Possum . It postulates that the symptoms of the disease, particularly positive symptoms, are due to abnormalities in dopaminergic neurotransmission. The theory was partially based on the fact dopamine mimetic drugs such as L-DOPA and amphetamines produce psychotic symptoms such as hallucinations and delusions.
Evidence for this theory includes findings such as the inhibitory effect of neuroleptics on the dopaminergic system as well as the direct correlation between the effectiveness of the drug and the affinity of the drug to Dopamine receptor, particularly D2 receptors . It has also been shown that in drug naive Schizophrenic patients (patients who have never been medicated for Schizophrenia), there is an increase in dopamine synthesis and presynaptic storage in the striatal region of the brain . PET scans have also shown increased striatal dopamine receptor D2 levels in schizophrenic patients . Moreover, increased dopaminergic activity is associated with the onset of psychotic symptoms in schizophrenia . These results, along with the fact that dopamine mimetic drugs produce psychotic symptoms such as hallucination provides strong evidence for this theory. Regions of the brain that are innervated by dopaminergic neurons such as the thalamus and the cortex are also affected in schizophrenic patients, both regions showing dopaminergic abnormalities .
While the above results account for the positive symptoms, the hypothesis has evolved over time to accommodate the negative symptoms. It postulates that hypo-activity of dopaminergic neurons in the prefrontal region may be responsible for the negative symptoms of schizophrenia .
But despite the evident importance of the dopaminergic system in Schizophrenia, the dopamine hypothesis cannot account for the whole range of symptoms associated with Schizophrenia. Also, infrequent reports, studies that have shown contradictory reports and the fact that very few replicative studies have been done to substantiate the above results contribute towards making the hypothesis somewhat controversial.
|Image 2: NMDAR inhibition leads to increased AMPAR activity|
While it is evident that dopamine plays a crucial role in schizophrenia, there exist other hypotheses that provide alternative mechanisms. One such hypothesis is the Glutamatergic Hypothesis. The hypothesis posits that dysfunction of glutamatergic neurons leads to schizophrenic symptoms. Glutamate is the primary excitatory neurotransmitter in our brain. Glutamate receptor consists of two classes of receptors: ionotropic receptors, ion channels that are activated directly by ligands, and metabotropic receptors, G-protein coupled receptors that involve secondary messengers. The ionotropic receptors are further divided into two types: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors or AMPAR) and N-Methyl-D-aspartate receptors (NMDAR).
The hypothesis was first proposed by Kim et al, in 1980 based on their finding of low glutamate level in the cerebrospinal fluid of schizophrenia patients, although this idea was at first disregarded as replication studies could not reproduce these findings. Despite its bad start, the hypothesis did gain some credit after the discovery of NMDAR antagonists such as phencyclidine and ketamine  (see Drug use and Schizophrenia ), which resulted in marked psychotic symptoms in healthy volunteers as well as aggravation of schizophrenic symptoms in patients . It is postulated that dopaminergic abnormalities is secondary to an underlying glutamatergic abnormality or dysfunction as NMDAR antagonists are also potent activators of dopamine release . Also, schizophrenic symptoms caused by NMDAR antagonists persist in the absence of dopaminergic activity  or dopamine antagonists .
Since glutamatergic neurons are not localized to any particular region in the brain but are distributed throughout the cortical and subcortical regions, dysfunction in the system affects cortical connections . As a result, deficit in cognitive processes, which is a marked symptom of schizophrenia, is observed.
Until recently, glutamate hypo-function was the focus of research, however over the last two decades; glutamate hyper-function is hypothesized to be involved in Schizophrenia. Inhibition of NMDAR at levels that cause cognitive deficits results in increased glutamate release . This results in increased neurotransmission through receptors other than NMDAR, mainly AMPAR. Based on these findings along with the fact that different receptors lead to different downstream signal cascades, it is suggested that cognitive defects are not a result of generalized hypo-function of NMDAR but may be the result of the hyper-function of AMPAR or other glutamate receptors .
Glutamate neurons synapse on GABA interneurons. GABA interneurons are critical for the regulation of hippocampal and neocortical pyramidal neurons. Lack of GABAergic inhibition would lead to hyperactivity of the pyramidal cells. This inhibition is critical for cognitive processes and is a classic example of feed forward inhibition where the excitatory input onto these interneurons results in the inhibition of pyramidal cells. Presence of NMDAR antagonists result in decreased GABAergic activity which leads to increased pyramidal neuronal firing . This in turn leads to increase glutamate levels resulting in increased AMPAR activation . This disturbance in the balance of excitation and inhibition of pyramidal neurons compromises their information processing ability.
Role of GABAergic Neurons
|Image 3: Decreased GABAergic activity leads to disinhibition of glutamatergic neurons.
This leads to increased excitatory input to the pyramidal neurons in the prefrontal cortex.
Post mortem studies of Schizophrenic brains suggest that the disorder is associated with GABAergic dysfunction . It is hypothesized that GABAergic neurons play an important role in the synchronization of neuronal activity in the neocortex, which is essential for normal cognitive function. GAD (glutamic acid decarboxylase), which exists in two isoforms 65kDa and 67kDa, is an enzyme that is required for the biosynthesis of GABA from glutamate. In pathological studies, GAD is used as a marker for GABAergic neurons . Studies have shown that , in schizophrenic patients, the levels of GAD67 mRNA are significantly reduced not only in the dorsolateral prefrontal cortex (DLPFC)  but also in the primary visual cortex, anterior cingulate cortex, and the primary motor cortex , regions that are important for cognitive functions. As a result, there is a decrease in the enzyme levels . Schizophrenia is also associated with the decreased expression of parvalbumin, a calcium-binding protein, mRNA by GABAergic neurons .
The decrease in GAD67 mRNA expression may be responsible for GABA neuronal dysfunction. A likely cause for this decrease may be altered gene regulation at the transcriptional level. Studies have shown that altered histone methylation leads to altered transcription of GAD1 gene . This gene encodes for GAD67. This alteration in transcription and translation results in decreased GABA synthesis. As a result, GABA intravesicular concentration decreases, causing decreased GABA release and consequently smaller inhibitory postsynaptic current (IPSC). Smaller IPSCs lead to disinhibition of pyramidal neurons resulting in cognitive dysfunction.
GABAergic neurons have several potential compensatory mechanisms to increase IPSC amplitude and duration. One of them achieved by decreasing GAT1-mediated uptake of GABA on the presynaptic neuron , while the other involves the increase of GABA/ GABA-A receptors on the post synaptic neuron allowing for an increase in GABA -A receptor binding activity .
Other Neurotransmitter Systems
Cholinergic neurotransmission is important for both CNS and PNS functions. CNS functions involve cognitive functioning, sleep, memory and psychosis while a PNS functions involve smooth muscle control, heart rate control and blood flow. Cholinergic dysfunction could play a role in cognitive impairment (a symptom of schizophrenia) such a learning and memory problems.
Post-mortem CNS studies in schizophrenic patients show a decrease in cholinergic interneurons . Muscarinic cholinergic receptor M1 (a G-protein coupled receptor) mRNA levels are reported to be significantly decreased in the dorsolateral prefrontal cortex  as well as the superior prefrontal gyrus  in Schizophrenics. Recreational use of Arecoline (a muscarinic agonist), particularly in the practice of chewing beetle nut, is correlated with reduced negative and positive symptoms in Schizophrenia .
The role of serotonin, like dopamine and glutamate, was derived from pharmacological observations of drugs like LSD and its effect on human behavior. Serotonin (5-hydroxtryptamine, 5-HT) affects a variety of behaviors which are disturbed in Schizophrenia, namely cognition, perception, mood, sleep and pain sensitivity. Studies have shown a strong correlation between the affinities of hallucinogenic drugs for 5-HT2 receptors . It has been shown that these drugs act as partial agonists of 5-HT2 receptors, particularly 5-HT2A subtype . Postmortem studies have shown reduced 5-HT2A receptor level in the prefrontal cortex of schizophrenic patients . However, PET scans in drug-naive patients show no such correlation. An association has also been reported between 5-HT2A gene polymorphism and attention deficits in Schizophrenia . Increased serotonin levels in the striatum and prefrontal cortex have also been reported in schizophrenic patients . These studies have prompted research on whether serotonin receptor abnormalities exist in Schizophrenia.
One of the strongest evidence that serotonin dysfunction is involved in schizophrenia is the effectiveness of atypical antipsychotic drugs such as Clozapine and Risperidone, which act more as a serotonin receptor antagonist and less as dopamine receptor antagonist. These drugs provide better results in patients that show no improvement with typical antipsychotic drugs that are direct dopamine antagonists .
Serotonin system is intricately linked to the dopaminergic system. Since the dorsal raphe project serotoninergic inhibitory projections directly to the substantia nigra, dopaminergic activity decreases in the prefrontal cortex . This could account for some of the negative symptoms of the disorder.
Signal Transduction Pathways
|Figure 2: PI3-K/ Akt (Protein Kinase B, PKB) signal cascade|
Neurotransmitter systems and intracellular signal transduction are intricately linked to one another. While on one hand different neurotransmitter hypotheses are gaining momentum, on the other, signal transduction cascades are being shown to play an important role in alteration of cell behavior important during neurodevelopment that can/may eventually lead to Schizophrenia. Schizophrenia has been associated with the PI3-K (Phosphotidyl Insositide 3-Kinase) pathway.
PI3-K is critical for cellular processes that are central to the development of the nervous system such as cell migration, cell division, cell differentiation and axonal growth .
PI3-K phosphorylates phosphoinositides producing PIP2 (Phosphotidylinositol-3, 4-bisphosphate) and PIP3 (Phosphotidylinositol-3, 4, 5-triphosphate) which result in the downstream activation of monomeric GTPases that are required for the above mentioned cellular processes. Protein that are involved in cellular behavior such as Brain-derived neurotrophic factor (BDNF) , Neuregulin-1  and Erythropoietin  have been associated with cognitive dysfunction in Schizophrenia. These proteins along with drugs such as clozapine and risperidone have been shown to act via PI3-K signal transduction . Some of the downstream targets of PI3-K are V-akt murine thymoma viral oncogene homologue (Akt) and cAMP response element-binding protein (CREB), both of which are crucial for neurodevelopment, have been implicated in the pathology of the disorder  . Disruptive Akt1 signaling results in change in neurological and psychological behaviors such as hypo-plasticity, anxiety disorders, etc. A study focusing on the role of Akt1 and its effect on the hippocampus by deleting Akt1 in mice has shown that deficiency of Akt1 could lead to the dysfunction of the PI3-K signaling pathways that can eventually lead to schizophrenia .
Schizophrenia is a complex disorder that involves various abnormalities at the cellular and molecular level. Although unknown if these abnormalities are causal or not, it can be concluded that signal transduction, intracellular as well as intercellular, plays a critical role in its development.
Hallucinations in Psychopathology
Natural, Synthetic, and Endogenous Psychedelic Compounds
Neurotransmitter system and neural circuits governing sleep
Serotonin theory of Autism
Receptors in Addiction
Tagged for Failure- CREB, CBP and other molecules associated with memory disruption