Schizophrenia as variation in the sapiens-specific epigenetic instruction to the embryo.

The psychoses (schizophrenia and bipolar disorder) occur in all populations with approximately uniform incidence and sex-dependent age of onset. Core symptoms involve aspects of language; brain structural deviations are sex and hemisphere-related. Genetic predisposition is unaccounted for by linkage or association. The hypothesis is proposed that the 'missing heritability' is epigenetic in form and generated in meiosis on a species-specific XY chromosomal template. A duplication from Xq21.3 to Yp11.2 that occurred 6 million years ago is proposed as critical to hominin evolution. Within this block of homology the Protocadherin11XY gene pair is expressed as a cell surface adhesion factor in both X and Y forms; it has undergone a series of coding changes (16 in the Y sequence and 5 in the X including two to cysteines) in the hominin lineage. According to the hypothesis these sequence changes, together with one or more deletions and a paracentric inversion in the Y block, were successively selected; late events in this series established cerebral asymmetry (the 'torque') as the defining characteristic of the human brain. Built around this reference frame, an epigenetic message channels early development of the embryo in a sapiens-specific format. Diversity in meiotic pairing is postulated as the basis for species-specific deviations in development associated with psychosis.

Replication profile of PCDH11X and PCDH11Y, a gene pair located in the non-pseudoautosomal homologous region Xq21.3/Yp11.2.

In order to investigate the replication timing properties of PCDH11X and PCDH11Y, a pair of protocadherin genes located in the hominid-specific non-pseudoautosomal homologous region Xq21.3/Yp11.2, we conducted a FISH-based comparative study in different human and non-human primate (Gorilla gorilla) cell types. The replication profiles of three genes from different regions of chromosome X (ZFX, XIST and ATRX) were used as terms of reference. Particular emphasis was given to the evaluation of allelic replication asynchrony in relation to the inactivation status of each gene. The human cell types analysed include neuronal cells and ICF syndrome cells, considered to be a model system for the study of X inactivation. PCDH11 appeared to be generally characterized by replication asynchrony in both male and female cells, and no significant differences were observed between human and gorilla, in which this gene lacks X-Y homologous status. However, in differentiated human neuroblastoma and cerebral cortical cells PCDH11X replication profile showed a significant shift towards allelic synchrony. Our data are relevant to the complex relationship between X-inactivation, as a chromosome-wide phenomenon, and asynchrony of replication and expression status of single genes on chromosome X.

Absence of basal ganglia amino acid neuron deficits in schizophrenia in three collections of brains.

Amino acid (glutamatergic, GABAergic) neuron deficiency theories of schizophrenia offer plausible explanations of pathogenesis. However, reports of disease-related reductions in amino acid synthesizing enzymes in post-mortem brains are contradictory. We measured neuronal uptake sites for gamma-aminobutyric acid (GABA; [3H]nipecotic acid binding) and nerve terminal/glial uptake sites for L-glutamate (D-[3H aspartate binding) in three independent groups of post-mortem brains from patients with schizophrenia and control subjects. Measurements were also made of the phencyclidine site of the glutamate N-methyl-D-aspartate (NMDA) receptor. Samples from patients showed no reductions in the binding of [3H]nipecotic acid or D-[3H]aspartate in caudate, putamen or globus pallidus. On the contrary, some increased binding of both ligands was observed in patients in many comparisons with controls. There were no clear-cut changes in NMDA receptor binding. The most consistent change in the brain sets was increased [3H]nipecotic acid binding in caudate-putamen. This could be due to neuroleptic treatment. The findings produce no evidence that schizophrenia involves major loss of GABA neuron terminals in the basal ganglia or losses of corticostriatal glutamatergic projections.

Analysis of polyglutamine-coding repeats in the TATA-binding protein in different human populations and in patients with schizophrenia and bipolar affective disorder.

A new class of disease (including Huntington disease, Kennedy disease, and spinocerebellar ataxias types 1 and 3) results from abnormal expansions of CAG trinucleotides in the coding regions of genes. In all of these diseases the CAG repeats are thought to be translated into polyglutamine tracts. There is accumulating evidence arguing for CAG trinucleotide expansions as one of the causative disease mutations in schizophrenia and bipolar affective disorder. We and others believe that the TATA-binding protein (TBP) is an important candidate to investigate in these diseases as it contains a highly polymorphic stretch of glutamine codons, which are close to the threshold length where the polyglutamine tracts start to be associated with disease. Thus, we examined the lengths of this polyglutamine repeat in normal unrelated East Anglians, South African Blacks, sub-Saharan Africans mainly from Nigeria, and Asian Indians. We also examined 43 bipolar affective disorder patients and 65 schizophrenic patients. The range of polyglutamine tractlengths that we found in humans was from 26-42 codons. No patients with bipolar affective disorder and schizophrenia had abnormal expansions at this locus.

Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy.

Amyloid plaques, associated with argyrophilic dystrophic neurites, and cerebral amyloid angiopathy (CAA), but no neurofibrillary tangles, were found in the brains of three middle-aged marmoset monkeys that had been injected intracerebrally (ic) 6-7 yr earlier with brain tissue from a patient with early-onset Alzheimer's disease. Such changes were not found in the brains of three age-matched control marmosets. Immunochemically the amyloid plaques and CAA stained with antibody to beta (A4)-protein. The plaques and CAA displayed dichroic birefringence when stained with Congo red and viewed under polarized light. beta (A4)-amyloid plaques and CAA were also found in the brain of one of two marmosets injected ic 6 yr previously with brain tissue from a patient with prion disease with concomitant beta (A4)-amyloid plaques and CAA. An occasional beta (A4)-amyloid plaque was found in the brains of two of four marmosets injected ic > 4.5 yr previously with brain tissue from three elderly patients, two of whom had suspected (but untransmitted) CJD. No beta (A4)-amyloid plaques or CAA were found in six marmosets who were older than the injected animals, in four marmosets that had not developed spongiform encephalopathy (SE) having been injected several years previously with human brain tissue from three younger patients with suspected or atypical prion disease, or in 10 younger marmosets who had undergone various neurosurgical procedures. Seventeen marmosets injected in the same way with brain tissue from patients or animals with SE developed SE 17-49 mo after injection. These results suggest that beta (A4)-amyloidosis is a transmissible process comparable to the transmissibility of SE.

Evidence for the experimental transmission of cerebral beta-amyloidosis to primates.

The brains of three marmosets (Callithrix jacchus) injected intracerebrally 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease were found to contain moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy but no neurofibrillary tangles. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of three age-matched control marmosets from the same colony did not show these neuropathological features. The brain of one of two marmosets injected with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and cerebral amyloid angiopathy also showed beta-amyloid plaques and angiopathy but no spongiform encephalopathy. An occasional plaque was found in the brains of two of four marmosets injected with brain tissue from three elderly patients with age-related pathology, two of whom had an additional diagnosis of possible prion disease. Neither plaques nor cerebral amyloid angiopathy were found in six other marmosets who were older than the injected animals, in 12 further marmosets who were slightly younger but who had been injected several years previously with brain tissue which did not contain beta-amyloid, or in 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that cerebral beta-amyloidosis may be induced by the introduction of exogenous amyloid beta-protein.

Experimental induction of beta-amyloid plaques and cerebral angiopathy in primates.

Moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy (CAA) but no neurofibrillary tangles (NFTs) were found in the brains of 3 middle-aged common marmosets (Callithrix jacchus) inoculated intracerebrally (i.c.) 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of 3 age-matched control marmosets from the same colony did not show these neuropathological features. beta-amyloid plaques and CAA (but no spongiform encephalopathy) were also found in the brain of a marmoset inoculated with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and CAA. An occasional beta-amyloid plaque was found in the brains of two marmosets inoculated with brain tissue from elderly patients. No beta-amyloid plaques nor CAA were found in 6 other marmosets who were older than the inoculated marmosets, 10 further marmosets who were slightly younger but who had been inoculated several years previously with brain tissue which did not contain beta-amyloid, and 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that beta-amyloidosis is a transmissible process.

Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases.

The identification of defects in the prion protein (PrP) gene in families with inherited Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome allows presymptomatic diagnosis or exclusion of these disorders in subjects at risk. After counseling, PrP gene analysis was performed in three such individuals: two from families with a 144-bp insert and one with a point mutation at codon 102 in the PrP gene. The presence of a PrP gene defect was confirmed in one and excluded in two. Despite the potential problems of using PrP gene analysis in genetic prediction - specifically, uncertainty about penetrance and, generally, problems of presymptomatic testing in any inherited late-onset neurodegenerative disorder - we conclude that it has a role to play in improved genetic counseling for families with inherited prion diseases.

G proteins (Gi, Go) in the medial temporal lobe in schizophrenia: preliminary report of a neurochemical correlate of structural change.

We have measured the amount of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in 5 areas of the medial temporal lobe of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The material used has previously been shown to have asymmetrical structural abnormalities of the ventricular system. The amount of Gi or Go was reduced on the left side in the hippocampus, amygdala and parahippocampal gyrus, the difference reaching significance in the hippocampus. This data is the first report of a neurochemical correlate of the structural change in the brains of patients with schizophrenia. Decreased Gi or Go in hippocampus may relate to other reported neurochemical deficits or other transmembrane signalling abnormalities. Further investigations of these indices of secondary messenger function in relation to structural changes are indicated.

A "mock up" of schizophrenia: temporal lobe epilepsy and schizophrenia-like psychosis.

Schizophrenia-like psychoses occur more frequently than expected in patients with chronic temporal lobe epilepsy. We have analyzed pathological and clinical data from a series (n = 249) of temporal lobectomies to determine the factors that may relate to the development of schizophrenia-like psychosis. Schizophrenia-like psychoses did not occur at random; they were significantly associated with lesions that (1) originated in the fetus or perinatally, (2) affected neurons in the medial temporal lobe, and (3) gave an early age of first fit. Gangliogliomas--developmental lesions of the medial temporal lobe containing aberrant neurons--were disproportionately (p less than 0.001) associated with risk of psychosis. Schizophrenia-like psychoses arising preoperatively occurred more often (p = 0.1) with left-sided lesions. Asymmetry of lesion was not present in cases with postoperative psychoses. These findings are of interest in relation to recent studies suggesting that the structural abnormalities found in the brains of schizophrenics arise during fetal brain development.

The occurrence of organic disease of possible or probable aetiological significance in a population of 268 cases of first episode schizophrenia.

In a sample of 268 cases of first-episode schizophrenia, 15 patients were found to have organic disease which appeared relevant to the mental state. There were three cases of syphilis, two cases of sarcoidosis, three of alcohol excess and two of drug abuse. There was one case each of carcinoma of the lung, autoimmune multisystem disease, cerebral cysticercosis, thyroid disease and previous head injury. In this series, identified organic disease was associated with less than 6% of cases of schizophrenia.

Search for viral nucleic acid sequences in the post mortem brains of patients with schizophrenia and individuals who have committed suicide.

Molecular hybridisation has been used to screen several areas of post mortem brain from 20 patients with schizophrenia, 23 individuals who were suspected of having committed suicide and 21 control cases, for viral nucleic acids. Cloned probes were able to detect picogram levels of viral DNA and to quantify herpes simplex type 1 DNA from encephalitic brain, but no sequences hybridising to cytomegalovirus, varicella zoster virus, herpes simplex type I or JC or BK papovaviruses were detected in any of the experimental samples. These findings are discussed with reference to the viral hypothesis of the aetiology of psychiatric disease.

Integrated viral genes as potential pathogens in the functional psychoses.

According to the retrovirus-transposon hypothesis, psychosis is due to the expression of a pathogenic sequence (a "virogene") integrated in the genome and either inherited from an affected or predisposed parent or acquired in the course of reproduction by a genetic rearrangement (e.g. a transposition or the generation of a tandem repeat). The psychoses are viewed as a continuum extending from unipolar through bipolar and schizo-affective disorder to schizophrenia with increasing severity of defect, movement along this continuum occurring by such genetic rearrangements. The locus at which these changes take place is envisaged as related to the genetic determinants of cerebral lateralisation (the "cerebral dominance gene") the interaction between potential pathogen and growth factor gene having possible growth enhancing effects. Such beneficial effects may have ensured the survival of this "hot-spot" in the genome.