Neurophysiology of Schizophrenia

Dr. Shivan A.C. Mahabir DM. Psychiatry Part 1 Year 1 17 April, 2012

Schizophrenia

Genetics

The most likely explanation for the unusual genetic transmission of schizophreniaits high frequency of 1% and its partial penetranceis that the illness is polygenic, involving in any given case perhaps as many as 3 to 10 genes. As with other polygenic diseases, such as diabetes and hypertension, it is possible that one or all of the critical genes are simply allelic variationspolymorphismsof genes, each one of which by itself would not cause disease. Rather it is the combination of allelic polymorphisms in the context of a specific genetic background that is critical for the disease. DEGREE OF RELATION LIFETIME RISK OF (% OF GENES SHARED) DEVELOPING SCHIZOPHRENIA

MONOZYGOTIC TWIN (100%)

1ST DEGREE (50% ) 2ND DEGREE (25%) 3RD DEGREE (12.5% ) GENERAL POPULATION (0%)

48%
6% - 17% 2%- 6% 2% 1%

Anatomical Changes

Early in the disease there is a reduction in the blood flow to the left globus pallidus suggestive of a disturbance in the system that connects the basal ganglia to the frontal lobes. Second, there appears to be a disturbance in the frontal lobes themselves since blood flow does not increase during tests of frontal lobe function involving working memory, as it does in normal subjects. Third, the cortex of the medial temporal lobe is thinner and the anterior portion of the hippocampus is smaller than in normal people, especially on the left side, consistent with a defect in memory. Finally, the lateral and third ventricles are enlarged and there is widening of the sulci, especially in the thinner temporal lobe and in the frontal lobe, reflecting a reduction in the volume of this lobe as well.

Neurotransmitters

DOPAMINE:

Dopaminergic neurons are not randomly distributed in the brain but are organized into four major systems: the tuberoinfundibular, nigrostriatal, mesolimbic, and mesocortical systems. The dopaminergic nigrostriatal system contributes to the symptoms of Parkinson disease., EPSE, tardive dyskinesia. The dopaminergic mesolimbic system has its origin in cell bodies in the ventral tegmental area, which is medial and superior to the substantia nigra. These cells project to the mesial components of the limbic system: the nucleus accumbens, the ventral striatum, the nuclei of the stria terminalis, parts of the amygdala and hippocampus, the lateral septal nuclei, the entorhinal cortex, the mesial frontal cortex, and the anterior cingulate cortex. It has a role in emotions and memory. Carlsson proposed that the positive symptoms of

Neurotransmitters

Among the projections of the mesolimbic system, those to the nucleus accumbens are thought to be particularly important because of the extensive connections of this nucleus to the limbic system. The nucleus accumbens receives and integrates inputs from the amygdala, hippocampus, entorhinal area, anterior cingulate area, and parts of the temporal lobe. The mesolimbic dopaminergic projection to the nucleus accumbens is thought to modulate these inputs and thereby influence the output of the nucleus accumbens to its target regions: the ventral pallidum, septum, hypothalamus, anterior cingulate area, and frontal lobes. As we have seen, some of the input sources, in particular the hippocampus, and some of the output targets, such as the cingulate cortex and the frontal lobes are thought to be disturbed in schizophrenia. Overactive modulation of the integration of the inputs to the nucleus accumbens and of the output from it could contribute to positive symptoms of schizophrenia.

Neurotransmitters

Daniel Weinberger postulated that two dopaminergic systems are disturbed in different ways in schizophrenia.

First, an increase in activity in the mesolimbic pathway (perhaps through the D2 and D3 receptors and particularly through the D4 receptors) would account for the positive symptoms. Second, decreased activity of the mesocortical connections in the prefrontal cortex would account for the negative symptoms. Weinberger proposes that activity in the mesocortical pathway to the prefrontal cortex normally inhibits the mesolimbic pathway by feedback inhibition and that the primary defect in schizophrenia is a reduction in this activity, which leads to disinhibition and overactivity in the mesolimbic pathway.

Neurotransmitters

GLUTAMATE:

N -methyl-D-aspartate (NMDA) receptors are present on the dopaminergic axon terminals in the prefrontal cortex and enhance dopamine release from the terminals. Psychosis may be caused by inhibiting dopamine release eg PCP (mesocortical pathway)
In contrast, at the dopaminergic terminals in the nucleus accumbens PCP increases dopamine release and inhibits reuptake (mesolimbic pathway).

Neurotransmitters

GAMMA AMINO BUTYRIC ACID (GABA):

Abnormalities of GABA activity in schizophrenia have been consistently shown in the last ten years. Schizophrenia is associated with both decreased numbers and abnormalities in the distribution of GABAergic neurons in the cortex, particularly in the cortical laminae (Kaplan & Sadock, 1995). The precise role GABA plays in the pathogenesis of schizophrenia is not entirely clear. GABA appears to have an effect on regulation of dopamine levels in the brain, so it's possible that the GABA-dopamine interaction is responsible for some symptoms of the disease.

Neurotransmitters

ACETYLCHOLINE:

Strong support for a role of the muscarinic cholinergic system in schizophrenia comes from post-mortem and brain-imaging studies. Several post-mortem studies have consistently shown a significant decrease of muscarinic receptor density in different brain regions that are considered to be of crucial importance in the pathophysiology of schizophrenia eg. frontal cortex, basal ganglia and hippocampus. These results include significant decreases in specific subtypes of the muscarinic receptor (in particular M1).

Neurotransmitters

SEROTONIN

Though serotonin does appear to have a role in schizophrenia, the assumption that it is directly responsible is still in question. Many have now theorized that increased levels of serotonin in the prefrontal cortex will result in lower dopamine levels in the area. These reduced dopamine levels, which may be responsible for the negative symptoms of schizophrenia, appear to lead to increased levels of dopamine in secondary dopaminergic systems. The increased dopamine levels are most likely responsible for the positive symptoms of schizophrenia.

Neurotransmitters

NOREPINEPHRINE:

The raised levels of norepinephrine in schizophrenia are no longer in doubt. What norepinephrine's role is, however, what part its reward system plays, and to what extent it modulates dopamine levels is still under question. It is proposed that schizophrenia may be related to a defect in the noradrenergic reward system. Hyperactivity of the system would produce raised norepinephrine levels, which creates a state of heightened autonomic arousal. They have observed this state throughout all phases of the psychosis (Hemmings & Hemmings, 1978).

Stress-Diathesis Model

References
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Towards a muscarinic hypothesis of schizophreniaTJ Raedler, FP Bymaster, R Tandon, D Copolov and B Dean. Principles of Neural Science. 4th edition. Eric Kandel. Kaplan, H.I., & Sadock, B.J. (Eds.). (1995). Comprehensive Textbook of Psychiatry. Baltimore, MD: Williams & Wilkins.