Schizophrenia is a chronic, debilitating mental disorder affecting 1-2% of the global population. Symptoms are split into two types; 'positive' symptoms, including delusions and hallucinations, and 'negative' symptoms, including anhedonia and lack of motivation. Studies suggest that genetics, early environment, neurobiology, psychological and social processes are important contributory factors; some recreational and prescription drugs appear to cause or worsen symptoms. Several neurobiological alterations in brain structure, physiology and neurochemistry have been documented, along with an ever-increasing list of susceptibility genes.
Schizophrenia Research Product Areas
Pathogenesis of Schizophrenia
Schizophrenia has been associated with the dysregulation of many neurotransmitter systems. Excessive dopamine is the oldest and most widely accepted theory of the pathophysiology of schizophrenia and stems from identification of dopamine D2 receptor blockade as the mechanism of action of antipsychotics. Dopamine D2 binding sites are increased in schizophrenic brains, whilst there are prefrontal D1 deficits, which contributes to cognitive impairment. The current understanding suggests that a hyperactive mesolimbic and a hypoactive mesocortical dopamine system underlie the 'positive' and 'negative' symptoms respectively that are seen in schizophrenia.
In addition to dopamine, serotonin, glutamate, GABA and acetylcholine dysregulation have also been implicated in the pathogenesis of schizophrenia. Glutamatergic signaling is attenuated in schizophrenia and is characterized by a loss of NMDA receptor-mediated excitatory neurotransmission. GABA levels are also attenuated due to downregulation of GABA transporter (GAT) gene expression. There is a concordant upregulation of GABAA receptors, which may contribute to the alterations in neural synchrony and consequently working memory impairment.
Over the last twenty years there has been an explosion in the knowledge of the neurobiology of schizophrenia, yet a precise understanding of its etiology and pathogenesis has remained elusive.
CNS Changes in Schizophrenia
Numerous neuroanatomical alterations are seen in the brains of schizophrenic patients. At the gross level, overall brain volume and grey matter volume is reduced in schizophrenic brains and ventricular volume (particularly the third and fourth ventricles) is increased. These changes in brain structure are seen early after, and sometimes prior to, onset of symptoms and can be progressive. White matter volume is also decreased in brains of schizophrenic patients and is consistent with the cognitive deficits seen in this disease. Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis is prevalent in schizophrenics and this has been linked to an increase in the severity of the above structural changes. The structural changes seen are subtle and there is evidence to suggest that schizophrenia arises from minor abnormalities in neurodevelopment, such as disordered cortical neuron migration.
Susceptibility Genes for Schizophrenia
Schizophrenia genetics are complex and several genomic loci are likely to harbor genes conferring risk for this disease.
- DISC1 has emerged as a strong candidate for a susceptibility gene. The molecular and cellular interactions of DISC1 are critical for normal neuronal development and in the adult are implicated in neuronal signal transduction and plasticity. DISC1 polymorphisms are associated with altered hippocampal function and identification of this gene supports the notion that schizophrenia is a disorder of cortical development.
- Neuregulin 1 signals via ErbB receptors to regulate NMDA receptor density and has been implicated in neuronal differentiation and migration. In schizophrenia, neuregulin 1 signaling is enhanced, leading to NMDA receptor suppression, which is consistent with the glutamate hypofunction hypothesis.
- Dysbindin has been reported to influence glutamate neurotransmission and reduced levels of this protein have been found in schizophrenic brains.
- D-amino acid oxidase activator (DAOA) has also been associated with schizophrenia. DAOA activates D-amino acid oxidase (DAO), which is a coagonist at NMDA receptors.
- Catechol-O-methyltransferase (COMT) participates in dopamine clearance from synapses and has been implicated in regulation of neurotransmission related to schizophrenia. A functional polymorphism in the COMT gene alters activity of this enzyme and homozygosity correlates to increased dopamine levels in critical central synapses.
First line pharmacological intervention of schizophrenia currently employs atypical antipsychotics such as clozapine and amisulpride. Typical antipsychotics, such as the dopamine receptor antagonists chlorpromazine and haloperidol, have been available since the 1950s but are less commonly used now due to their adverse side effects. Antipsychotics are effective at reducing the 'positive' symptoms of this disease, but often have very little efficacy in reducing the 'negative' symptoms.
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Potent, selective LRRK2 inhibitor
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