Elementary phenotypes in the neurobiological and genetic study of schizophrenia

SCHIZOPHRENIA RESEARCH SERIES: NEURODEVELOPMENT AND PATHOPHYSIOLOGY Elementary Phenotypes in the Neurobiological and Genetic Study of Schizophrenia Lawrence E. Adler, Robert Freedman, Randal G. Ross, Ann Olincy, and Merilyne C. Waldo This review describes the strategy of using elementary phenotypes for neurobiological and genetic linkage studies of schizophrenia. The review concentrates on practical aspects of selecting the phenotype and then understanding the confounds in its measurement and interpretation. Examples from the authors’ studies of deficits in P50 inhibition and smooth pursuit eye movement dysfunction are presented. These two phenotypes share considerable similarity in their neurobiology, including a similar response to nicotine. They also appear to co-segregate with the genetic risk for schizophrenia as autosomal co-dominant phenotypes. Although most schizophrenic patients inherit these abnormalities unilinealy, i.e., from one parent, apparent bilineal inheritance produces a more severe illness, observed clinically as childhood-onset schizophrenia. The initial study showing linkage of the P50 deficit to the chromosome 15q14 locus of the ␣7-nicotinic acetylcholine receptor is an example of the potential usefulness of these phenotypes for combined genetic and neurobiological study of schizophrenia. Biol Psychiatry 1999;46: 8 –18 © 1999 Society of Biological Psychiatry Key Words: Neuronal inhibition, schizophrenia physiology, eye movements, auditory evoked potentials, genetic segregation, childhood-onset schizophrenia

Introduction

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he strategic decision to use elementary phenotypes for the genetic analysis of complex diseases such as schizophrenia involves several considerations. First, one must assume that the major genes for the illness are not readily resolved by linkage analysis or by direct sequencing of candidate genes. Second, one must decide that one or more specific biological phenomena are more likely to represent the inheritance of a major gene effect than the presence of the illness itself. For schizophrenia, neither of these issues have straightforward answers. Schizophrenia

From the Department of Psychiatry, University of Colorado Health Sciences Center and Denver VA Medical Center, Denver, CO (all authors). Address reprint requests to Lawrence E. Adler, MD, Department of Psychiatry, Campus Box C268-16, UCHSC, 4200 E. 9th Ave., Denver, CO 80262. Received October 16, 1998; revised March 29, 1999; accepted March 30, 1999.

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does not have Mendelian inheritance, so that the clinical illness is unlikely to represent the phenotype of a single major schizophrenia gene (Gottesman and Shields 1972; Tsuang et al 1990), although there is clearly a familial form of the illness (Kendler et al 1985). However, the power to detect smaller gene effects is enhanced by increasing the numbers of families under study and an increasing the precision of the human genome map. Both of these tactics are currently being employed for the study of schizophrenia. Thus, the ability to find major gene effects by linkage is not yet fully known. Candidate gene analysis has been less successful, but it is still a viable technique. Initial efforts to sequence genes thought to be involved in schizophrenia, such as a dopamine receptors, did not reveal any genetic abnormalities (Moldin 1997). However, these efforts were not an exhaustive examination of all the possible candidate genes and were necessarily limited by current hypotheses of the pathophysiology of schizophrenia. Indeed, because the biology of schizophrenia, as a brain illness, is likely complex, any gene in the genome is a candidate gene. Thus, as for linkage, the limiting factor is the power of the analysis in terms of the number of genes that are examined and the number of people that are sequenced. The principal strength of linkage analysis is that there is no reliance on biological hypotheses about the illness because all locations in the entire genome are considered equally likely to have a pathogenic role. To retain this advantage would seem desirable, but to discard all information about the biological nature of schizophrenia seems of dubious value (Lander 1988). As an example, it was the differentiation of biological subtypes that enabled breakthroughs in the genetic analysis of coronary artery disease, a disorder which, like schizophrenia is influenced by a number of different genetic and environmental factors (Goldstein et al 1973). Focusing on families with the highest serum glucose levels as a specific phenotype led to discovery of a genetic deficit that results in Type 2 diabetes (Mahtani et al 1996). The strategy of using an alternative, elementary neurobiological phenotype for the analysis of schizophrenia assumes that one or more major pathophysiologic deficits in the illness can be identified, 0006-3223/99/$20.00 PII S0006-3223(99)00085-2

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and that these deficits can be related to a single underlying neuronal deficit. Thus, the use of elementary phenotypes is primarily a biological strategy. The strategy then attempts to take advantage of the power of genetic analysis by using linkage and candidate gene analysis to determine if the biological deficit is, in fact, caused by a deficit in a specific gene (Arolt et al 1996; Blackwood et al 1991; Holzman et al 1988; Kong and Cox 1997; Sham et al 1994; Shihabuddin et al 1996). To date, this approach has not succeeded in uncovering a specific genetic deficit, however, significant linkage results have been obtained using one phenotype, a deficit in the inhibition of the P50 auditory evoked response to repeated stimuli (Freedman et al 1997). The number of phenotypes that can be examined using these methods is certainly not limited to this one abnormality, so that it may be worthwhile for other biological researchers to consider this strategy. In particular, the ability to prove or disprove the heritability of a particular biological abnormality in schizophrenia provides an additional test of the validity of hypotheses about the biology of the schizophrenia, which heretofore has not been possible. Finally, a significant advantage for basing genetic linkage studies on a specific phenotype other than diagnosis, is that greater statistical power can be obtained with than might otherwise be the case (NIMH Genetics Workshop 1997). This aspect has been discussed in a previous paper (Freedman et al 1999).

Attentional Dysfunction in Schizophrenia The multitude of theories about the biology of schizophrenia is a testimony to the fundamental uncertainty about the nature of the illness. Diagnostic criteria combine subjective and objective reports with an assessment of a prolonged clinical course, none of which points to a pathognomonic functional difficulty. Yet, there are profound and readily recognizable differences between schizophrenic patients and any other medical diagnosis (Kendler et al 1985). Several authorities have pointed to attentional dysfunction as an important pathophysiologic entity that could explain much of the clinical presentation of schizophrenia (Venables 1964). Schizophrenic subjects describe a specific difficulty in keeping their attention focused on a particular object and complain about the intrusion of unwanted sensory information (McGhie and Chapman 1961; Park et al 1995). Such difficulties are highly correlated with the psychosocial decline that is critical to the diagnosis and clinical outcome of the illness (Cornblatt and Keilp 1994; De Amicis et al 1986; Green et al 1996, 1997). Despite this literature and the clinical experience, distractibility itself is listed as a diagnostic criterion for both mania and attention deficit disorder, but not for schizophrenia, in DSM-IV (APA 1994). Indeed, bipolar

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patients, when manic, also manifest such distractibility. Thus even at the clinical level, it is difficult to develop a biological representation of schizophrenia that is sufficiently specific to support genetic analysis. A critical decision with the P50 auditory evoked response was to recognize the similarities and differences in attentional disturbance in mania and schizophrenia and to attempt to develop a biological explanation that would help us increase the specificity of the P50 measure for each illness. The attentional dysfunction associated with psychosis is consistent with a loss of inhibitory function, which is the neuronal substrate normally associated with discrimination between stimuli. To characterize inhibition, neurophysiologists frequently use a conditioning-testing paradigm, in which paired stimuli are presented (Eccles 1969). The first stimulus activates excitatory inputs that cause a neuronal response, such as the P50 response, which is a positive wave occurring 50 msec after an auditory stimulus. The first stimulus also activates or conditions inhibitory pathways. These inhibitory pathways are activated too late to affect the amplitude of the response to the conditioning stimulus, but if a second stimulus is presented soon thereafter, then that the second response is suppressed by the inhibitory mechanisms still active from the conditioning response. The length of time for which the inhibition remains active varies with the type of inhibitory neuronal mechanism. For example, monosynaptic GABAA-mediated inhibition rarely lasts longer than 50 msec, whereas GABAB-mediated inhibition can last up to 300 msec (Hershman et al 1995). Because loss of inhibition at the 500 msec inter-stimulus interval maximally distinguished schizophrenic patients from normal control subjects (Adler et al 1982; Nagamoto et al 1989), multisynaptic pathways are likely to be involved. A number of studies have examined the effect of the stage or character of illness on P50 suppression in schizophrenia. Acutely, there appears to be no effect of typical neuroleptic medication on P50 ratio (Adler et al 1990a). Thus, the deficit is unlikely to reflect an abnormality in catecholaminergic neuronal transmission. However, individuals treated with atypical neuroleptics exhibit normalization of their P50 ratio coincident with improvement in their clinical symptoms (Nagamoto et al 1996, 1999). Yee and co-workers (1998) also noted that treatment with atypical neuroleptics improves P50 suppression in recent onset patients. Erwin and colleagues, on the other hand, noted that deficits in P50 suppression in their paradigm was related to a history of exposure to neuroleptic drugs (Erwin et al 1994). Yee and co-workers (1998), Erwin and co-workers (1998), Vinogradov and colleagues (1996), and Cullum and co-workers (1993) found that impaired P50 suppression was most pronounced in subjects with clinical or neurophysiologic evidence for abnormal atten-

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tional and linguistic function. Jin and colleagues (1998), however, found that patients’ self-report of attentional dysfunction was not related to the presence of a deficit in P50 suppression. Finally, P50 gating deficits in families of schizophrenic patients occur in a manner consistent with possible autosomal dominance (Siegel et al 1984; Waldo et al 1991). Deficits are found not only in schizophrenic patients, but also in many of their first-degree relatives, including apparent obligate carriers (Waldo et al 1995; Young et al 1996), and confirmed by other groups (Clementz et al 1998b). Thus, the deficit likely reflects a genetically transmitted abnormality.

The Measurement of P50 Sensory Gating Abnormalities The suppression of the P50 response to repeated auditory stimuli had been observed in normal subjects prior to our finding of an abnormality of this function in schizophrenia (Chapman et al 1981; Davis et al 1996; Erwin and Buchwald 1986; Finkenzeller and Keidel 1975; Fruhstorfer et al 1970; Jerger et al 1992; Papanicolau et al 1985; Roth and Kopell 1969). Diminished suppression of P50 in schizophrenia, compared to normal control subjects, has been observed by Erwin and co-workers (1991), Boutros and co-workers (1991), Braff and Geyer (1990), Judd and co-workers (1992), Clementz and colleagues (1997), Jin and colleagues (1997), Lambert and colleagues (1993), and Yee and co-workers (1998). Kathmann and Engel (1990) found no suppression in both the normal control and the schizophrenic subjects. Despite the general convergence of findings, there are significant differences between laboratories in both the stimulation paradigm and the methods for the analysis of the evoked response. One difference is the use of stimulus trains, as opposed to paired stimuli, which have shown diminished suppression of P50 by schizophrenic subjects in some (Erwin et al 1991) but not all studies (Grillon et al 1991). A second difference is the use of multiple recording sites, instead of a single vertex electrode (Judd et al 1992; Clementz et al 1998a; Cardenas et al 1993). Although the wave is maximally recorded at the vertex, the use of these other sites to compute a single vector improves the reliability of the measure (Cardenas et al 1993). Problems in test-retest reliability have been noted by several investigators (Smith et al 1994). In addition to the use of multiple recording sites, assessment of confounding state factors such as increased catecholaminergic activity due to stress has been helpful in reducing inter-trial variance, as described further in this article. The selection of the ratio of the amplitudes the two responses (amplitude of the test response to amplitude of the conditioning response) as the primary variable has also

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received considerable discussion. Ratios have inherent problems in reproducibility because of their mathematical properties (Cardenas et al 1993; Smith et al 1994). For example, all cerebral evoked potential measurements include both a signal and a noise component. A ratio measurement that includes noise in both the numerator and denominator will approach an assymptote of 1, as the noise increases. Smith and colleagues compared analysis of the individual amplitudes in various combinations to ratios and found that although the ratio has the lowest test-retest reliability in normal subjects, nevertheless the ratio measurement has the greatest power for distinguishing normal subjects from schizophrenic subjects (Smith et al 1994). Many investigators have been concerned about the lower amplitude of the P50 response to the first stimulus in schizophrenic subjects, compared to normal subjects. Straumanis and co-workers noted that the P50 wave increased in amplitude during neuroleptic treatment (Straumanis et al 1982). This finding was replicated in Freedman and co-workers (1983) and Adler and colleagues (1990a) studies, both of which found that the abnormality in the ratio of the two amplitudes is unchanged when schizophrenic patients are treated with typical neuroleptic drugs, despite the increase in the initial P50 response amplitude to normal levels. Because the latency of the wave is also reduced in unmedicated schizophrenic patients, the smaller wave was hypothesized to reflect a hyperexcitable neuronal substrate, which results in less synchronization of the response to stimuli and hence, a smaller evoked potential. A similar hypothesis led several groups to attempt single trial analyses, rather than relying on the averaged evoked response to a set of stimuli, to detect the relatively greater amount of desynchronization. Freedman and co-workers (1996) pointed out the difficulty of separating signal from noise using an automated single trial analysis technique. However, Zouridakis and co-workers (1997) and Jin and colleagues (1997), using other single trial analysis techniques, concluded that the diminished response to the first response, as well as the defect in gating, is heavily influenced by the loss of synchronization in the response to stimuli. Because all evoked potential techniques include significant amounts of noise in their signal, inherent in the indirect nature of recording neuronal activity at the scalp surface, assessment of the noise component is critical before a firm conclusion about the nature of single-trial responses can be made (Arpaia et al 1989).

Clinical Determinants of P50 Suppression The P50 gating deficit is also found in bipolar subjects. Although inhibition is normal in both euthymic and depressed bipolar patients, acutely manic bipolar patients have a failure of inhibition in the manic state that resem-

Elementary Phenotypes in Schizophrenia

bles that seen in schizophrenia (Adler et al 1990a; Franks et al 1983). However, there are important clinical differences. The P50 gating deficit is found in both predominantly positive symptom and predominantly negative symptom schizophrenic patients (Adler et al 1990b). Similar P50 gating deficits are found in acutely ill schizophrenic inpatients (Adler et al 1982, 1990a; Ward et al 1996) and more stable schizophrenic outpatients with less psychosocial impairment (Freedman et al 1983; Ward et al 1996). Manic patients, on the other hand, lose their inhibitory deficit in concert with their successful treatment (Adler et al 1990a). Because manic patients are known to have elevated catecholamine metabolism as part of the pathophysiology of their illness, we measured their plasma levels of the norepinephrine metabolite 3-methoxy,4-hydroxy phenylethylene glycol (MHPG) prior to and after treatment with neuroleptics and lithium carbonate. Prior to treatment, their plasma-free MHPG levels were increased compared to matched normal subjects, which also coincided with impaired P50 inhibition. P50 gating improved as plasma-free MHPG decreased toward normal with medication treatment (Adler et al 1990a). Mania is not the only disorder that can result in a transient P50 auditory gating deficit. Almost half of psychiatric inpatients have diminished P50 auditory gating acutely, but most, except the schizophrenic patients, return to more normal P50 inhibitory gating during the course of hospitalization (Baker et al 1987). Post-traumatic stress disorder can also result in impaired P50 auditory gating as well (Adler et al 1991; Gillette et al 1997). Cocaine abuse also causes a transient P50 auditory gating deficit (Adler et al, unpublished data 1999; Fein et al 1996). Because P50 auditory gating in normal subjects can also change with moderately severe stress or with catecholaminergic manipulation (see below), impaired P50 auditory gating is not diagnostic of schizophrenia. It is useful as a phenotypic marker in family members of schizophrenic patients, only with the assurance that they are otherwise clinically normal. There is one report which suggests that females have higher T/C ratios than males, but the p value (p ⫽ .08) was not significant (Hetrick et al 1996). In contrast, we found that even female patients with premenstrual syndrome have unimpaired P50 auditory gating, although they have rated themselves as being distressed at the time of recording (Waldo et al 1987). P50 auditory gating is normalized in most subjects by late adolescence (Freedman et al 1987; MylesWorsley et al 1996) and remains unimpaired through age 65. After that age, loss of inhibition has been reported in normal aging adults (Papanicolau et al 1984).

Noradrenergic Mechanisms in Sensory Inhibition The studies in mania, cocaine addiction, and normal subjects under stress, suggested that increased noradren-

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ergic neuronal transmission is one of the principal confounds for use of P50 inhibition as a trait marker for studies of schizophrenia. Therefore, we performed a series of animal experiments to determine if increased noradrenergic neuronal transmission disrupts sensory gating. Normal rats inhibit the auditory evoked response to repeated stimuli with parameters highly similar to those that characterize the human inhibition (Adler et al 1986, 1988; Bickford-Wimer et al 1990). The skull surface wave in rats has a major source in the CA3 region of the hippocampus (Bickford-Wimer et al 1990). Human P50 can be recorded in the hippocampus (Freedman et al 1994a), and single neurons recorded in both human and rat hippocampus show a decremented response to repeated sounds (Miller and Freedman 1995; Wilson et al 1984). Recordings at both the skull surface and in the hippocampus in rats were performed while noradrenergic neurotransmission was manipulated pharmacologically. Manipulations that increased noradrenergic neuronal transmission resulted in loss of inhibition of the auditory evoked response (Adler et al 1986, 1988; Bickford-Wimer et al 1990). One such treatment was the administration of phencyclidine, which releases norepinephrine via its effects on sigma opiate receptors and causes loss of auditory evoked potential inhibition. Because phencyclidine has other effects, such as antagonism of NMDA-glutamate receptors, the study was repeated in animals in which the noradrenergic terminals had been previously lesioned with a specific neurotoxin, DSP-4 (Adler et al 1988; Miller et al 1992). In these lesioned animals, phencyclidine had no effect on auditory evoked potential inhibition. Similar results occurred with dextroamphetamine treatment, i.e., dextroamphetamine impaired auditory evoked potential inhibition, and its effect was also blocked by pretreatment with DSP-4 (Adler et al 1986, 1988; Bickford-Wimer et al 1990). Another, more specific, treatment was the administration of yohimbine, which causes the release of norepinephrine by the blockade of the alpha-2 presynaptic noradrenergic receptors that normally inhibit norepinephrine release. Yohimbine administration caused loss of auditory evoked potential gating in rats (Stevens et al 1993). These pharmacologic effects are consistent with other neurophysiologic evidence that suggests that the primary effect of norepinephrine in the hippocampus is loss of inhibition (Madison and Nicoll 1988). This effect interacts with the polysynaptic mechanism responsible for inhibition at the 500 msec interval between stimuli. The yohimbine experiment was repeated in normal human subjects. As was found in the rats, yohimbine decreased the inhibition of the P50 evoked potential, thus validating the results of the animal model and the hypothesis of a causal relationship between loss of inhibition of the P50 potential and increased noradrenergic neurotrans-

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mission in mania (Adler et al 1994). Elevated noradrenergic neurotransmission can also occur in normal subjects when they are under stress. The stress can be purposely introduced into the experimental paradigm (Johnson and Adler 1993) or it can be an unintended by-product of an unfamiliar experimental situation involving complicated equipment in a hospital environment (Waldo et al 1994). We found that normal subjects frequently have decreased P50 inhibition during initial recordings in these circumstances. This improvement in inhibition occurs as they gain familiarity with the recording environment. Their gain in inhibition also correlates with a decrease in plasma free MHPG levels (Waldo et al 1994). Finally, schizophrenic subjects themselves can have a similar phenomenon. Although MHPG levels are not a major determinant of their abnormality in inhibition, nonetheless there is some correlation with plasma MHPG levels (Kang et al 1997). This mechanism may be one part of the effects of clozapine on the inhibition of the auditory evoked potential. Unlike typical neuroleptics, clozapine normalizes auditory evoked potential inhibition in some schizophrenic patients (Nagamoto et al 1996), in parallel with a positive clinical response and a decrease in MHPG levels (Nagamoto et al 1999). An essay on the effects of norepinephrine on the P50 auditory evoked potential seems only tangentially related to the search for genes related to schizophrenia. In fact, there are few phenotypes that are strictly determined from meiosis, without any effect of moment-to-moment changes in the environment, influences from other genes, or both. The P50 inhibition phenotype is no exception. This paper has described only one of many influences on its measurement. Effects of alcohol (Freedman et al 1986), nicotine (Adler et al 1992, 1993), sleep (Griffith et al 1993, 1995a), stimulus intensity (Griffith et al 1995b), EEG filter settings (Freedman et al 1998), development (Benes 1997; Eslinger et al 1997; Freedman et al 1994; Myles-Worsley et al 1996), medications (Adler et al 1990a,b; Freedman et al 1983; Nagamoto et al 1996; Straumanis et al 1982; Ward et al 1996), brain lesions (Bickford and Wear 1995), traumatic brain injury (Arciniegas et al in press; Scheibel and Levin 1997), and aging (Papanicolau et al 1984) must all be considered by investigators intending to use this or any other phenotype for the study of schizophrenia. Similar considerations have been noted to be of importance in another well-studied ERP phenotype, the P300 (Pfefferbaum et al 1989).

jects, 95% had ratios of the amplitude of the test response to the amplitude of the conditioning response less than .50. For schizophrenic patients, 95% had ratios greater than .40. Ratios less than or equal to .40 were therefore considered normal, and ratios greater than or equal to .50 were considered abnormal. Ratios in between (.41 to .49) were considered unknown (Freedman et al 1997). Because ratios have difficult mathematical properties, in terms of skewness and, in this case, a number of 0 values (normals), these qualitative values were used for segregation analysis. The segregation analysis, performed by the SAGE programs (Elston 1996), was consistent with the autosomal dominant effect of a single gene. The disease allele frequency was assumed to be .05, with penetrance .80 in either the homozygous or heterozygous state, consistent with autosomal dominant inheritance. The rate of phenocopies, abnormal P50 ratios occurring in individuals with normal genotypes, was assumed to be .01. These assumptions yield a prevalence for elevated P50 ratio of 8.7% of the population, with 10.4% of the elevated P50 ratios being phenocopies. The prevalence is consistent with our previous samples of normal populations (Waldo et al 1994). This model was significantly more likely than the assumption of no genetic transmission (p ⬍ 6.53 ⫻ 10 ⫺10 ) or a recessive model (p ⬍ 1.51 ⫻ 10 ⫺5 ), or for a simple additive model, which might have been expected if the trait were multigenic (Freedman et al 1997; Kong and Cox 1997). An initial linkage analysis with this model showed some evidence for linkage of impaired P50 inhibitory gating with markers in the chromosome 15q14 area (Coon et al 1993). Later, this area was also shown to be the locus of the ␣7-nicotinic acetylcholine receptor subunit gene, which animal models had suggested was involved in the cholinergic activation of interneurons in the hippocampus (Chini et al 1994). Subsequent linkage analysis showed linkage to D15S1360, a polymorphic dinucleotide repeat marker in the chromosome 15q14 region, identified in a yeast artificial chromosome that contains the ␣7nicotinic cholinergic receptor (Freedman et al 1997). Linkage to this region of 15q14 has been further supported by analysis of the inheritance of schizophrenia in the NIMH Genetics Initiative families (Leonard et al 1998). At this point, because of the complexity of the gene itself (Gault et al 1998), no corresponding molecular abnormality has yet been found in the region of linkage, so that the genetic basis for inheritance of the P50 abnormality or schizophrenia has yet to be determined.

Genetic Linkage Using the P50 Phenotype P50 ratios from schizophrenic patients, their relatives, and normal subjects, were entered into a segregation analysis. The 95% confidence levels for both normal subjects and schizophrenic patients were determined. For normal sub-

Familial Transmission of Other Abnormalities in Schizophrenia Although the search for a molecular abnormality in the 15q14 region is still in progress, the results with the P50

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phenotype appear positive enough to suggest that the strategy of identifying specific phenotypes in the schizophrenia spectrum may have advantages for both biological and genetic research. Therefore, we have begun a more systematic search for other elementary neuronal phenotypes. Some of them may simply be improved P50 inhibition measurements, which will allow even more powerful genetic analysis, but will continue to identify the chromosome 15q14 locus. Some may identify other loci. For example, various eye-tracking dysfunctions have been shown to co-segregate with a previously identified linkage on chromosome 6 (Arolt et al 1996), and cerebral atrophy in one family has been shown to co-segregate with a schizophrenia-associated locus on chromosome 5 (Shihabuddin et al 1996). Radant and Hommer (1992) reported that schizophrenic patients have intrusions of small anticipatory saccades into their smooth-pursuit tracking and that this phenomenon is a more robust discriminator between schizophrenic and normal subjects than other measures of dysfunction. This measure, often quantify as either the frequency of saccades or the percentage of eye movement due to the saccades, is relatively stable during middle childhood development (ages 8 to 13 years) and thus suitable for phenotypic studies before the age of onset of schizophrenia (Ross et al 1993). Furthermore, the preliminary indication is that the measure is distributed in families in a pattern consistent with an autosomal dominant trait. It is present in half the offspring of schizophrenic parents, and it is found in parents who have been identified as obligate carriers as described previously (Ross et al 1998a,b; 1999a,b,c). Although the intrusion of small anticipatory saccades into smooth pursuit is not the only defect in smoothpursuit eye-movement function in schizophrenia, this deficit shares three characteristics with the P50 inhibitory deficit. First, both deficits can be conceptualized as inhibitory deficits. Second, both deficits are expressed in parents who are apparent obligate carriers of the genes that convey a risk for schizophrenia (Ross et al 1998a,b; 1999a,b,c). Third, both deficits are normalized in schizophrenic patients by high doses of nicotine, such as those that occur due to the patients’ own smoking (Olincy et al 1998). The anticipatory saccades and smooth-pursuit eye movements themselves both move the eye in the direction of the target. The smaller anticipatory saccades, in particular, seem to be responsive to the general instruction to track the target. Although there is some failure of the smooth-pursuit system, as measured by the increased percentage of eye movement accounted for by catch-up saccades in schizophrenic subjects, the intrusion of anticipatory saccades is a more prominent feature in schizophrenia, as judged by the differences in effect sizes (Ross et al 1999c). These findings suggest that the most signif-

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icant portion of the global failure of eye-movement function is failure to inhibit the intrusion of these saccades. Basic neurophysiologic studies point to the cerebellar cortex as an area in which signals for both types of eye movements appear and perhaps arrive at the site where the decision about which type to use is made (Pierrot-Deseilligny 1994).

Possible Co-Dominant Inheritance of the Physiologic Abnormalities in ChildhoodOnset Schizophrenia The distribution of the elementary neurophysiologic phenotypes, and even of neuropsychological measures of attention, in schizophrenic patients and their parents is consistent with autosomal dominant inheritance. In other words, one parent, generally the one with an ancestral family history of schizophrenia, is the carrier of this abnormality, which is then also found in the schizophrenic offspring (Harris et al 1996; Ross et al 1998a,b; Siegel et al 1984). Even in families without an identifiable ancestral history, generally one, and only one, parent carries the neurophysiologic or neuropsychological abnormality (Waldo et al 1995). True genetic dominance means that the phenotypic abnormality is identical, regardless of whether an individual inherits only one or both abnormal alleles. Both the linkage and segregation studies, as well as the family studies, we have performed to date suggest that the inheritance of the P50 abnormality and of the anticipatory saccade abnormality is dominant (Freedman et al 1997). Inheritance of two abnormal alleles can only be rigorously established once molecular deficits have been identified. However, most geneticists who are looking for such homozygous inheritance would examine individuals with an early onset of illness, as such individuals generally inherit a more severe form of illness as well. Such a generic description of homozygous inheritance actually fits the clinical description of childhood-onset schizophrenia well (Alaghband-Rad et al 1995; McKenna et al 1994). The illness is rare, which is to be expected if two genetic abnormalities are required, and it has the requisite early onset and greater severity, while still resembling the putative more common heterozygous version of the illness, i.e., adult onset schizophrenia. We examined 10 cases of childhood-onset schizophrenia and their two parents. While we did not assess genetic inheritance, we could compare the frequency of bilineal appearance of the two physiologic phenotypes, the P50 auditory gating deficit and the increased anticipatory saccades in the parents of the proband to the usual unilineal appearance in adult-onset schizophrenia. We found bilineal appearance of elevated anticipatory sac-

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cades in 8 of 10 pairs of parents, and bilineal appearance of P50 inhibitory abnormalities in 6 of 10. A corollary is that the neurophysiologic phenotypes should be more severely abnormal in the homozygous individuals, in this case, in the childhood-onset schizophrenic patients. We observed this effect for the eye-tracking abnormality. The percent of eye movement due to anticipatory saccades in these childhood-onset schizophrenic patients was approximately twice as great as that observed in adult-onset schizophrenic subjects (Ross et al 1998c). Thus, there is preliminary evidence that this abnormality is inherited in a co-dominant, rather than in a strict dominant, fashion. Furthermore, these results suggest a pathogenic mechanism, bilineal inheritance, that was not previously obvious in this puzzling variant of schizophrenia.

Conclusion This paper attempted to develop some of the practical issues in choosing phenotypes for the genetic and neurobiological study of schizophrenia. The initial clinical observation of an attention deficit in schizophrenia and its operational redefinition in neuronal terms, using the conditioning-testing paradigm was a critical step. Difficulties in specificity were resolved by the combination of clinical and animal model studies that provided critical data confirming a clinical effect of nicotine on P50 auditory gating and the mediating role of the 2-7 nicotine receptor (Adler et al 1992, 1993, 1998; Bickford and Wear 1995; Breese et al 1997a,b; Frazier et al 1997; Freedman et al 1995; Luntz-Leybman and Freedman 1992; Griffith et al 1998; Olincy et al 1997, 1999; Stevens et al 1996; Stevens and Wear 1997; Stevens et al 1998). Similar difficulties arise with other phenotypes, as demonstrated by the difficulty in determining the exact nature of dysfunction in eye-movement function (Ross et al 1998a,b). Convergence in genetic and neurobiological findings between the two phenotypes, in terms of their pattern of segregation and their response to nicotine, is encouraging. The different segregation pattern of both phenotypes in childhood-onset schizophrenia may be especially revealing. This paper did not attempt to review the technical problems of linkage analysis itself, as it applies to the use of physiologic phenotypes. That discussion occurs in another review article that appears earlier in Biological Psychiatry (Freedman et al 1999). This paper, similarly, did not attempt to review the vast body of work on physiologic dysfunction in schizophrenia from other authors, many of whom have made seminal contributions to this field. That discussion occurs in a chapter in the CD ROM version of Psychopharmacology: A Fourth Generation of Progress (Freedman et al 1999).

This work was presented at the conference, “Schizophrenia: From Molecule to Public Policy,” held in Santa Fe, New Mexico in October 1998. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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