Neurophysiology of Schizophrenia

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

Schizophrenia .

it is possible that one or all of the critical genes are simply allelic variations—polymorphisms—of genes. As with other polygenic diseases. each one of which by itself would not cause disease.6% 2% 1% .Genetics  The most likely explanation for the unusual genetic transmission of schizophrenia—its high frequency of 1% and its partial penetrance—is that the illness is polygenic.17% 2%. Rather it is the combination of allelic polymorphisms in the context of a specific genetic background that is critical for the disease.5% ) GENERAL POPULATION (0%) 48% 6% . DEGREE OF RELATION LIFETIME RISK OF (% OF GENES SHARED) DEVELOPING SCHIZOPHRENIA MONOZYGOTIC TWIN (100%) 1ST DEGREE (50% ) 2ND DEGREE (25%) 3RD DEGREE (12. involving in any given case perhaps as many as 3 to 10 genes. such as diabetes and hypertension.

the cortex of the medial temporal lobe is thinner and the anterior portion of the hippocampus is smaller than in normal people. especially in the thinner temporal lobe and in the frontal lobe. as it does in normal subjects. the lateral and third ventricles are enlarged and there is widening of the sulci. Third. Finally. consistent with a defect in memory.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. 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.    . Second. reflecting a reduction in the volume of this lobe as well. especially on the left side.

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

and frontal lobes. . anterior cingulate area.Neurotransmitters   Among the projections of the mesolimbic system. hypothalamus. septum. As we have seen. some of the input sources. anterior cingulate area. entorhinal area. and some of the output targets. those to the nucleus accumbens are thought to be particularly important because of the extensive connections of this nucleus to the limbic system. hippocampus. such as the cingulate cortex and the frontal lobes are thought to be disturbed in schizophrenia. and parts of the temporal lobe. in particular the hippocampus. The nucleus accumbens receives and integrates inputs from the amygdala. 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. 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.

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. decreased activity of the mesocortical connections in the prefrontal cortex would account for the negative symptoms. . Second.Neurotransmitters  Daniel Weinberger postulated that two dopaminergic systems are disturbed in different ways in schizophrenia. 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.    First.

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).

particularly in the cortical laminae (Kaplan & Sadock. 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.Neurotransmitters  GAMMA AMINO BUTYRIC ACID (GABA):   Abnormalities of GABA activity in schizophrenia have been consistently shown in the last ten years. . so it's possible that the GABA-dopamine interaction is responsible for some symptoms of the disease. Schizophrenia is associated with both decreased numbers and abnormalities in the distribution of GABAergic neurons in the cortex. 1995).

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. These results include significant decreases in specific subtypes of the muscarinic receptor (in particular M1). basal ganglia and hippocampus.Neurotransmitters  ACETYLCHOLINE:    Strong support for a role of the muscarinic cholinergic system in schizophrenia comes from post-mortem and brain-imaging studies.

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

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

Stress-Diathesis Model .

Comprehensive Textbook of Psychiatry.References 1. Baltimore. Principles of Neural Science. Kaplan.J.I. Eric Kandel.). (Eds. FP Bymaster. MD: Williams & Wilkins. H. R Tandon. (1995). 3. 2. D Copolov and B Dean.. & Sadock. Towards a muscarinic hypothesis of schizophreniaTJ Raedler. 4th edition. . B.

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