- Email: [email protected]
A neuronal model for learned helplessness in the rat
SATURDAY,, MAY 21
gressive changes in ventricular size in schizophrenia have yielded inconsistent results. However, most of these studies did not subclassify patients according to the outcome of the illness. The present cross-sectional study examined lateral ventricular, frontal, and posterior horn VBRs in the CT scans of 122 chronic schizophrenic patients and 79 normal control subjects. The schizophrenic patients were sub-grouped to poor outcome ':Kraepalinian" (Nt-.56) and relatively good outcome "non-Kraepelinian" (N2-66) patients. Significant enlargement of all three ventricular regions were found in the schizophrenic group, when compared to normal controls (MANOVA: F 2 t97 "9.30, p
325. EFFECT OF CORTICAL GRAY MATI'ER, ATTENTION AND SCHIZOPHRENIA ON P300 AMPLITUDE J.M. Ford, D.H. Mathalon, E.V. Sullivan, K.O. Lim, & A. Pfefferbaum Stanford University School of Medicine and Department of Veterans Affairs, Palo Alto, CA 94304 The amplitude of the P300 component of the event-related brain potential (ERP) is affected by attention (Donchin, 198 I) but is also related to cortical gray matter volumes (Ford et al., 1993). Smaller P300s (Ford et al., 1991) and smaller cortical gray matter brain volumes (Zipursky et al., 1992) are often reported in schizophrenics (SZ). This report addresses the contribution of diagnosis, attentional systems, and total cortical gray matter volume to P300 amplitude. We collected ERPs and MR! from 18 unmedicated SZ men and 28 age- and sex-matched normal control subjects (NCS). ERPs were elicited during three auditory paradigms invoking three attentional systems: effortful, automatic, and effortful+automatic attention. P300 amplitude was measured over the parietal lobe (Pz). MRIderived measures taken from axial images estimated total cortical gray matter volumes, in a 2-way ANOVA (diagnosis x attentional system) there were significant effects of diagnosis and attention, but not for their interaction, suggesting an overall reduction in P300 amplitude in SZ and a tendency for the P300 elicited automatically to be smaller than the others irrespective of diagnosis. Correlational analyses showed that in NCS, gray matter volume was significantly related to P300 during effortful and automatic+effortful attention, but not during automatic attention. In SZ, these relationships were not significant. However, when the slopes of the regression lines relating P300 amplitude to gray matter were compared across groups and attentional systems, only during effortful+antomatic attention was there a trend for the slopes to differ (p<.08), with a positive slope emerging in NCS but not in SZ. Finally, diagnosis, cortical gray matter volume, and attention exerted statistically independent influences on P300 amplitude. Thus, the reduction of P300 amplitude in SZ remains even after conlxolling for the effects of cortical gray matter and attention. Perhaps because of the small sample sizes, we were unable to demonstrate
BIOLPSYCHIATRY 705 1994;35:615-747
that the relationship between cortical gray matter and P300 amplitude depended significantly on diagnosis or attention. Nevertheless, there were trends suggesting that the contribution of gray matter to P300 amplitude was less pronounced in SZ, especially during the task invoking both effortful and automatic attention. These trends may reflect differences in brain resources available, ability to recruit available brain resources, or strategies invoked to perform the task. [Supported by MH30854 and DVA]
326. MRI CHANGES IN ELDERLY SCHIZOPHRENIC, DEPRESSIVE, AND CONTROL SUBJECTS M.S. Keshavan, B. Mulsant, R.R. Krishnan, R.A. Sweet, A.H. Rifai, R. Pasternak, & G.S. Zubenko Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA The aim of this study was to examine cerebral changes on magnetic resonance imaging (MRI) scans in elderly subjects with schizophrenia and major depression. We compa~l 20 subjects with schizophrenia, 19 ageand gender-matched subjects with major depression, and ! 9 age- and gunder-matched non-psychiatric controls using MRI. All psychiatric diagnoses had been established as per DSM-IlI-R, using consensus diagnostic conferences. MR! scans were evaluated using the Fazekas Rating Scale, as well as a more detailed rating scale developed at Duke University Medical Center. MRi scans were evaluated independently by two raters (MSK and BM) who had good to excellent inter-rater reliability. No statistically significant differences in total ratings were found between the three groups even though there was a trend for more abnormalities to be seen in the schizophrenic group (p-0.097). No significant differences were seen between the groups in regard to either the total deep white matter hyperintensity or periventricular hyperintensity lesions. The extent of deep white matter lesions was significantly higher in the schizophrenic group in the right posterior regions (p-0.03). The total Fazekas ratings were significantly related to age in normal (p-0.03)and schizophrenic subjects (p-0.009) but not in the delaessed group. Age of onset was positively associated with total Fazekas ratings in the depressive group (p-0.01) but not in the schizophrenia group, it is possible that MR! cerebral changes described in elderly depressives in previous li~:rature may be more specific to late-onset depression. Larger systematic studies of early- and lateonset depression in late life are needed to further examine this question.
327. A NEURONAL MODEL FOR LEARNED HELPLESSNESS IN THE RAT F. Pettyt,2, G.L. Kramerl, & S. Jordan 2 tDepartment of Veterans Affairs Medical Center;, 2Department of Psychiatry, UT Southwestern Medical School, Dallas, TX 75216 Learned helplessness is a maladaptive behavior resulting from exposure to inescapable stress. Learned helplessness (LH) in the rat has been proposed as an animal model of depression although some of its features may model anxiety and post traumatic stress disorder as well. We have proposed a multitransmitter, multiregion brain map as the neurocbemical and neuroanatomicai basis for learned helplessness development, prevention, and reversal. Recently, we have used in vivomicrodialysis to confirm and extend the neuronal model. The development of learned helplessness begins with a nonspecific activation of dopamine in the medial prefrontal cortex (MPC) in response to stress. Semtonin (5-HT) is subsequently released, leading to eventual profound depletion of intraneuronal stores, but
706
BIOL PSYCHIATRY 1994;35:615-747
only in rats developing learned helplessness. This cortical (5-HT) deficit can be prevented by prior training in escapable stress, by benzodiazepines, or subchronic tficyclic antidepressants 0~CA), via a GABAergic locus in M[~. Helplessness can also be reversed by cortical injection of TCA or of 5-l-IT. The hippocampus (IIPC) is also involved in LII with GABA both preventing and reversing LH and GABA blockade causing LH. Norepinephrine (NE) has a paradoxical effect in HPC, with NE release preventing LH but NE depletion correlating with LH. Septal 5-HT is key to LH reversal with TCA, and hypothalamus receives septohippocampal efferents with 5-HT and NE interactions hypothesized to mediate LI-I. Since LH is itself stressful, a maladaptive cycle is perpetuated, leading to subehronic behavioral deficits. Clinical predictions of the LH model will be discussed.
328. PREDICTIVE VALIDITY OF FSL RAT, AN ANIMAL MODEL OF DEPRESSION D.H. Overstreet, O. Pucilowski, D.S. Janowsky, & A.H. Rezvani Center for Alcohol Studies and Department of Psychiatry, University of North Carolina, Chapel Hill NC 27599-7175 The Hinders Sensitive Line (FSL) rat has been proposed as a genetic animal model of depression because it exhibits increased REM sleep amount, reduced REM sleep latency, increased sensitivity to the behavioral and hormonal effects of cholinergic agonists, and reduced activity in an open field relative to the control, Hinders Resistant Line (FRL) rat. in addition, the FSL rat shows an exaggerated immobility when exposed to mild stres. sots such as an inescapable swim tank and mild foot shock and a greater reduction in saccharin preference (anhedonia) when exposed to chronic mild stress. There is also some limited data that FSL rats "respond" to classical tricyclic antidepressants by increasing their mobility in the swim test. The present series of experiments sought to extend these observations by examining both newer generations antidepressants such as serotonin reuptake inhibitors (false negatives in the standard swim test) and calcium channel blockers and stimulants such as amphetamine and scopolamine (false positives in the standard swim test). The FSL and FRL rats were treated for 14 days twice daily with either desipramine (5 mg/ kg) setlraline (5.7 mg/kg), amphetamine (2 mg/kg), scopolamine (2 rag/ kg), verapamil (5 and 15 nWkg), nicardipine (2.5 and tO mg/kg), or vehicle. The single session, S-rain swim test was conducted 24 hr after the last injection. Under these conditions, only desipramine significantly lowered the very low immobility scores of the FRL rats. In contrast, desipramine, sertraline, verapamil (both doses) and nicardipine (10 mg/kg only) all reduced immobility in the FSL rats, while the stimulants amphetamine and scopolamine had no significant effects. In separate studies it was confirmed that acute or chronically administered scopolamine dramatically increased mobility in the FSL rats when given 30 rain before the swim test. These Findings show that the FSL rats exhibit a p~luction in immobility following chronic treatment with sertraline, a promising new generation antidepressant, desipramine, a classical tricyclic antidepressant, and two calcium channel blockers, which have also been recently reported to have antidepressant potential. Thus, support for the predictive validity of the FSL rat model of depression has been obtained,
329. POSTNATAL _REMODELING OF MONKEY PREFRONTAL CORTICAL CIRCUITRY S.A. Anderson 1, J. Classey2, J.S. Lund2, F. Cond~ I, & D.A. Lewis I University of Pittsburgh, Pittsburgh, PA, 15213; 2University of
SATURDAY, MAY 21
London, London, England Normal cortical development in prin~te.~ appears to involve an initial overproduction of synapses, followed by synapse elimination until adult levels are achieved. It has been suggested ~.batan abnormality in cortical synapse elimination in humans could be involved ;n rite pathophysiology of schizophrenia. Previous electron microscopy studies i~ primate cortex have demonstrated that these changes in synaptic deJ~sity primarily involve asymmetric, presumably excitatory synapses, the majority of which are located on the dendritic spines of pyramidal neurons. The timing of synapse reduction remains unclear, but may occur largely during adolescence. However, the timing and extent of changes of synaptic input to subpopulations of pyramidal neurons have not been determined. In this study, the rapid Golgi technique was used to identify pyramidal neurons in mid-layer !il of areas 9 and 46 of monkey (Macacamulatta) prefrontal cortex. Spine density was found to increase substantially during the first months of life, remain fairly stable between 3 and 18 months of age, and then decline markedly during adolescence. For example, on the apical dendritic tree, spine density decreased 30% between prepubertal and adult animals. Similar reductions in spine density were found on basal dendrites. Immunohistochemical experiments revealed that chandelier neuron axon cartridges, an important source of inhibitory input to these pyramidal neurons, may also undergo a parallel pattern of overproduction and elimination. Since mid-layer !!! pyramidal neurons in prefrontal cortex are critical components of corticocortical information processing, these findings may be relevant to the hypothesis that schizophrenia can result from an abnormality in the process of synapse elimination during adolescence.
330. GENETIC DIFFERENCES IN BEHAVIORAL RESPONSE TO NEONATAL HIPPOCAMPAL DAMAGE IN RATS B.K. Lipska & D.R. Weinberger Clinical Brain Disorders Branch, NIMH, Neuroscience Center at St. Elizabeths, WashingtOn DC 20032 The principal clinical phenomena associated with schizophrenia including postpubertal onset, developmental structural hippocampal abnormality, frontal cortical dysfunction, dysregulation of t,'ze limbic dopaminergic (DA) system and vulnerability to stress have been difficult to explain by a unitary animal model. We recently described a model that may address these features. Excitotoxic ventral hippocampal (VH) lesions induced in neonatal (postnatal day 7, PDT) Sprague-Dawley (SD) male rats do not affect behavioral indices of DA transmission before puberty (PD35), but result in the postpubertal (PD56) emergence of striatal/limbic DA hyperresponsivity. There is important evidence of genetic liability to schizophrenia. Genetic factors that control brain function may be studied in genetically inbred strains of rats. it has been demonstrated that two strains of rats - SD and Fischer F344 (F) differ in responsiveness to stress and in functional states of the mesolimbie DA system. We now report that behavioral effects of neonatal VH lesions differ substantially between these two strains. A similar lesion in terms of size (appr. 50-75% of hippocampal area destroyed) and location (VII) induces more exaggerated locomotor hyperactivity in response to a novel environment and to amphetamine in F rats than in SD rats. Moreover, in contrast to SD rats, in F rats the effects appear early (PD35). On the other hand, a more restricted VH damage confined to appr. 10% of hippocampal area results in postpubertal emergence of hyperactivity in F rats. These data suggest that the developmental lesion may interact with genetic factors involved in dopaminergic function. This could also be the case in schizophrenia where probably several risk factors, such as perinatal hippocampal defect and genetic as well as environmental components, account for the onset of the illness.
gressive changes in ventricular size in schizophrenia have yielded inconsistent results. However, most of these studies did not subclassify patients according to the outcome of the illness. The present cross-sectional study examined lateral ventricular, frontal, and posterior horn VBRs in the CT scans of 122 chronic schizophrenic patients and 79 normal control subjects. The schizophrenic patients were sub-grouped to poor outcome ':Kraepalinian" (Nt-.56) and relatively good outcome "non-Kraepelinian" (N2-66) patients. Significant enlargement of all three ventricular regions were found in the schizophrenic group, when compared to normal controls (MANOVA: F 2 t97 "9.30, p
325. EFFECT OF CORTICAL GRAY MATI'ER, ATTENTION AND SCHIZOPHRENIA ON P300 AMPLITUDE J.M. Ford, D.H. Mathalon, E.V. Sullivan, K.O. Lim, & A. Pfefferbaum Stanford University School of Medicine and Department of Veterans Affairs, Palo Alto, CA 94304 The amplitude of the P300 component of the event-related brain potential (ERP) is affected by attention (Donchin, 198 I) but is also related to cortical gray matter volumes (Ford et al., 1993). Smaller P300s (Ford et al., 1991) and smaller cortical gray matter brain volumes (Zipursky et al., 1992) are often reported in schizophrenics (SZ). This report addresses the contribution of diagnosis, attentional systems, and total cortical gray matter volume to P300 amplitude. We collected ERPs and MR! from 18 unmedicated SZ men and 28 age- and sex-matched normal control subjects (NCS). ERPs were elicited during three auditory paradigms invoking three attentional systems: effortful, automatic, and effortful+automatic attention. P300 amplitude was measured over the parietal lobe (Pz). MRIderived measures taken from axial images estimated total cortical gray matter volumes, in a 2-way ANOVA (diagnosis x attentional system) there were significant effects of diagnosis and attention, but not for their interaction, suggesting an overall reduction in P300 amplitude in SZ and a tendency for the P300 elicited automatically to be smaller than the others irrespective of diagnosis. Correlational analyses showed that in NCS, gray matter volume was significantly related to P300 during effortful and automatic+effortful attention, but not during automatic attention. In SZ, these relationships were not significant. However, when the slopes of the regression lines relating P300 amplitude to gray matter were compared across groups and attentional systems, only during effortful+antomatic attention was there a trend for the slopes to differ (p<.08), with a positive slope emerging in NCS but not in SZ. Finally, diagnosis, cortical gray matter volume, and attention exerted statistically independent influences on P300 amplitude. Thus, the reduction of P300 amplitude in SZ remains even after conlxolling for the effects of cortical gray matter and attention. Perhaps because of the small sample sizes, we were unable to demonstrate
BIOLPSYCHIATRY 705 1994;35:615-747
that the relationship between cortical gray matter and P300 amplitude depended significantly on diagnosis or attention. Nevertheless, there were trends suggesting that the contribution of gray matter to P300 amplitude was less pronounced in SZ, especially during the task invoking both effortful and automatic attention. These trends may reflect differences in brain resources available, ability to recruit available brain resources, or strategies invoked to perform the task. [Supported by MH30854 and DVA]
326. MRI CHANGES IN ELDERLY SCHIZOPHRENIC, DEPRESSIVE, AND CONTROL SUBJECTS M.S. Keshavan, B. Mulsant, R.R. Krishnan, R.A. Sweet, A.H. Rifai, R. Pasternak, & G.S. Zubenko Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA The aim of this study was to examine cerebral changes on magnetic resonance imaging (MRI) scans in elderly subjects with schizophrenia and major depression. We compa~l 20 subjects with schizophrenia, 19 ageand gender-matched subjects with major depression, and ! 9 age- and gunder-matched non-psychiatric controls using MRI. All psychiatric diagnoses had been established as per DSM-IlI-R, using consensus diagnostic conferences. MR! scans were evaluated using the Fazekas Rating Scale, as well as a more detailed rating scale developed at Duke University Medical Center. MRi scans were evaluated independently by two raters (MSK and BM) who had good to excellent inter-rater reliability. No statistically significant differences in total ratings were found between the three groups even though there was a trend for more abnormalities to be seen in the schizophrenic group (p-0.097). No significant differences were seen between the groups in regard to either the total deep white matter hyperintensity or periventricular hyperintensity lesions. The extent of deep white matter lesions was significantly higher in the schizophrenic group in the right posterior regions (p-0.03). The total Fazekas ratings were significantly related to age in normal (p-0.03)and schizophrenic subjects (p-0.009) but not in the delaessed group. Age of onset was positively associated with total Fazekas ratings in the depressive group (p-0.01) but not in the schizophrenia group, it is possible that MR! cerebral changes described in elderly depressives in previous li~:rature may be more specific to late-onset depression. Larger systematic studies of early- and lateonset depression in late life are needed to further examine this question.
327. A NEURONAL MODEL FOR LEARNED HELPLESSNESS IN THE RAT F. Pettyt,2, G.L. Kramerl, & S. Jordan 2 tDepartment of Veterans Affairs Medical Center;, 2Department of Psychiatry, UT Southwestern Medical School, Dallas, TX 75216 Learned helplessness is a maladaptive behavior resulting from exposure to inescapable stress. Learned helplessness (LH) in the rat has been proposed as an animal model of depression although some of its features may model anxiety and post traumatic stress disorder as well. We have proposed a multitransmitter, multiregion brain map as the neurocbemical and neuroanatomicai basis for learned helplessness development, prevention, and reversal. Recently, we have used in vivomicrodialysis to confirm and extend the neuronal model. The development of learned helplessness begins with a nonspecific activation of dopamine in the medial prefrontal cortex (MPC) in response to stress. Semtonin (5-HT) is subsequently released, leading to eventual profound depletion of intraneuronal stores, but
706
BIOL PSYCHIATRY 1994;35:615-747
only in rats developing learned helplessness. This cortical (5-HT) deficit can be prevented by prior training in escapable stress, by benzodiazepines, or subchronic tficyclic antidepressants 0~CA), via a GABAergic locus in M[~. Helplessness can also be reversed by cortical injection of TCA or of 5-l-IT. The hippocampus (IIPC) is also involved in LII with GABA both preventing and reversing LH and GABA blockade causing LH. Norepinephrine (NE) has a paradoxical effect in HPC, with NE release preventing LH but NE depletion correlating with LH. Septal 5-HT is key to LH reversal with TCA, and hypothalamus receives septohippocampal efferents with 5-HT and NE interactions hypothesized to mediate LI-I. Since LH is itself stressful, a maladaptive cycle is perpetuated, leading to subehronic behavioral deficits. Clinical predictions of the LH model will be discussed.
328. PREDICTIVE VALIDITY OF FSL RAT, AN ANIMAL MODEL OF DEPRESSION D.H. Overstreet, O. Pucilowski, D.S. Janowsky, & A.H. Rezvani Center for Alcohol Studies and Department of Psychiatry, University of North Carolina, Chapel Hill NC 27599-7175 The Hinders Sensitive Line (FSL) rat has been proposed as a genetic animal model of depression because it exhibits increased REM sleep amount, reduced REM sleep latency, increased sensitivity to the behavioral and hormonal effects of cholinergic agonists, and reduced activity in an open field relative to the control, Hinders Resistant Line (FRL) rat. in addition, the FSL rat shows an exaggerated immobility when exposed to mild stres. sots such as an inescapable swim tank and mild foot shock and a greater reduction in saccharin preference (anhedonia) when exposed to chronic mild stress. There is also some limited data that FSL rats "respond" to classical tricyclic antidepressants by increasing their mobility in the swim test. The present series of experiments sought to extend these observations by examining both newer generations antidepressants such as serotonin reuptake inhibitors (false negatives in the standard swim test) and calcium channel blockers and stimulants such as amphetamine and scopolamine (false positives in the standard swim test). The FSL and FRL rats were treated for 14 days twice daily with either desipramine (5 mg/ kg) setlraline (5.7 mg/kg), amphetamine (2 mg/kg), scopolamine (2 rag/ kg), verapamil (5 and 15 nWkg), nicardipine (2.5 and tO mg/kg), or vehicle. The single session, S-rain swim test was conducted 24 hr after the last injection. Under these conditions, only desipramine significantly lowered the very low immobility scores of the FRL rats. In contrast, desipramine, sertraline, verapamil (both doses) and nicardipine (10 mg/kg only) all reduced immobility in the FSL rats, while the stimulants amphetamine and scopolamine had no significant effects. In separate studies it was confirmed that acute or chronically administered scopolamine dramatically increased mobility in the FSL rats when given 30 rain before the swim test. These Findings show that the FSL rats exhibit a p~luction in immobility following chronic treatment with sertraline, a promising new generation antidepressant, desipramine, a classical tricyclic antidepressant, and two calcium channel blockers, which have also been recently reported to have antidepressant potential. Thus, support for the predictive validity of the FSL rat model of depression has been obtained,
329. POSTNATAL _REMODELING OF MONKEY PREFRONTAL CORTICAL CIRCUITRY S.A. Anderson 1, J. Classey2, J.S. Lund2, F. Cond~ I, & D.A. Lewis I University of Pittsburgh, Pittsburgh, PA, 15213; 2University of
SATURDAY, MAY 21
London, London, England Normal cortical development in prin~te.~ appears to involve an initial overproduction of synapses, followed by synapse elimination until adult levels are achieved. It has been suggested ~.batan abnormality in cortical synapse elimination in humans could be involved ;n rite pathophysiology of schizophrenia. Previous electron microscopy studies i~ primate cortex have demonstrated that these changes in synaptic deJ~sity primarily involve asymmetric, presumably excitatory synapses, the majority of which are located on the dendritic spines of pyramidal neurons. The timing of synapse reduction remains unclear, but may occur largely during adolescence. However, the timing and extent of changes of synaptic input to subpopulations of pyramidal neurons have not been determined. In this study, the rapid Golgi technique was used to identify pyramidal neurons in mid-layer !il of areas 9 and 46 of monkey (Macacamulatta) prefrontal cortex. Spine density was found to increase substantially during the first months of life, remain fairly stable between 3 and 18 months of age, and then decline markedly during adolescence. For example, on the apical dendritic tree, spine density decreased 30% between prepubertal and adult animals. Similar reductions in spine density were found on basal dendrites. Immunohistochemical experiments revealed that chandelier neuron axon cartridges, an important source of inhibitory input to these pyramidal neurons, may also undergo a parallel pattern of overproduction and elimination. Since mid-layer !!! pyramidal neurons in prefrontal cortex are critical components of corticocortical information processing, these findings may be relevant to the hypothesis that schizophrenia can result from an abnormality in the process of synapse elimination during adolescence.
330. GENETIC DIFFERENCES IN BEHAVIORAL RESPONSE TO NEONATAL HIPPOCAMPAL DAMAGE IN RATS B.K. Lipska & D.R. Weinberger Clinical Brain Disorders Branch, NIMH, Neuroscience Center at St. Elizabeths, WashingtOn DC 20032 The principal clinical phenomena associated with schizophrenia including postpubertal onset, developmental structural hippocampal abnormality, frontal cortical dysfunction, dysregulation of t,'ze limbic dopaminergic (DA) system and vulnerability to stress have been difficult to explain by a unitary animal model. We recently described a model that may address these features. Excitotoxic ventral hippocampal (VH) lesions induced in neonatal (postnatal day 7, PDT) Sprague-Dawley (SD) male rats do not affect behavioral indices of DA transmission before puberty (PD35), but result in the postpubertal (PD56) emergence of striatal/limbic DA hyperresponsivity. There is important evidence of genetic liability to schizophrenia. Genetic factors that control brain function may be studied in genetically inbred strains of rats. it has been demonstrated that two strains of rats - SD and Fischer F344 (F) differ in responsiveness to stress and in functional states of the mesolimbie DA system. We now report that behavioral effects of neonatal VH lesions differ substantially between these two strains. A similar lesion in terms of size (appr. 50-75% of hippocampal area destroyed) and location (VII) induces more exaggerated locomotor hyperactivity in response to a novel environment and to amphetamine in F rats than in SD rats. Moreover, in contrast to SD rats, in F rats the effects appear early (PD35). On the other hand, a more restricted VH damage confined to appr. 10% of hippocampal area results in postpubertal emergence of hyperactivity in F rats. These data suggest that the developmental lesion may interact with genetic factors involved in dopaminergic function. This could also be the case in schizophrenia where probably several risk factors, such as perinatal hippocampal defect and genetic as well as environmental components, account for the onset of the illness.