CLINICAL HANDBOOK OF SCHIZOPHRENIA

3. Biological Theories 27cortex (in correlation with negative symptoms) and auditory cortex of the superior temporalgyrus (in correlation with hallucinations). In comparison studies of monozygotictwins, the affected sibling shows smaller whole-brain volume overall, enlarged third andlateral ventricles, and specific volume reduction in the hippocampus and frontal lobes.The limitations of volumetric studies should be noted here. First, they do not specifythe microscopic pathology present in a region of reduced volume. Second, they may failto identify regions where subtle pathology exists without reducing overall volume (e.g.,ectopy or miswiring). Third, it is currently unclear how the macroscopic abnormalities ofschizophrenia lead to positive, negative, and cognitive symptoms. Nonetheless, all of theevidence leaves little doubt that schizophrenia is a “brain disorder,” though none of theseabnormalities at the moment are pathognomonic or diagnostic.Microscopic AbnormalitiesMicroscopic abnormalities in schizophrenia have been suggested in several regions, includinghippocampus and entorhinal cortex, anterior cingulate cortex, and prefrontalcortex. Changes in gross neuron size and number have been reported, as well as a varietyof changes in neuronal organization and structure. The significance of these findings iscurrently uncertain.There is more revealing evidence for developmental abnormalities of the cortex atthe microscopic level. Neurons migrate into the cortex in an “inside-out manner” duringdevelopment; early neurons form lower cortical layers, and later neurons migrate throughthese from below to form higher cortical layers. Studies of frontal cortex, entorhinal cortex,and limbic cortex show reduced numbers of certain neuronal types in higher corticallayers. Instead, these neurons appear in lower layers, or even in subcortical white matter,as if their migration had arrested too early. Because this stage of neural migration occursduring the second trimester of pregnancy, the timing is coincident with many knownschizophrenia risk factors. Abnormal neural migration in schizophrenia is likely to be apromising area for future research.Genetic FactorsOf all known risk factors for schizophrenia, family history is the most powerful. The heritabilityof schizophrenia, or total variability explained by all genetic factors, is 81%.Monozygotic twins are 40–50% concordant for schizophrenia compared to 10% for fraternaltwins. The risk of schizophrenia survives adoption into families without schizophrenia.These findings indicate that the genome carries a substantial share of the burdenof schizophrenia risk, but these findings do not specify which particular genes bear thebrunt of the burden.Recently, genomewide linkage and association studies have revealed a steadily growingset of candidate genes for schizophrenia risk. Their functions are diverse, but thesegenes fall into two broad categories: neurotransmission and neurodevelopment/plasticity.In the neurotransmission category, risk-conferring genes include an overactive allelefor the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT), proposedto cause dopamine deficiency resulting in prefrontal dysfunction leading to cognitive andnegative symptoms; underactive alleles for dysbindin, which are proposed to interfere withglutamate neurotransmission at the postsynaptic level; underexpression of the gene RGS4,thought to interfere with the guanine nucleotide–binding protein (G-protein) signalingpathway used by dopamine and some glutamate receptors; dysfunctional alleles of the genesG72 and GRM3, thought to alter glutamate neurotransmission in the hippocampus andprefrontal cortex, thereby giving rise to the cognitive abnormalities seen in schizophrenia.