- Email: [email protected]
Neuropathology of schizophrenia
Research aspects
Neuropathology of schizophrenia
in living patients (Table 1). Alterations are present in patients experiencing their first episode, and some also in at-risk subjects, indicating that there is a pathology that cannot be explained away as an artefact of chronic illness and that is in some way related to the disorder itself. A simple but informative measure is brain size, with brain volume being reduced by about 3–4% based upon meta-analyses of the MRI literature, and brain weight by a similar amount as measured at post-mortem examination.1 Neuropathological studies have sought to explain the smaller brain, and to attempt to localize and characterize the histological and cellular correlates of schizophrenia.
Paul J Harrison
Abstract
The neuropathology is not degenerative
It is no longer tenable to view schizophrenia as a ‘functional’ disorder, lacking any structural involvement of the brain. There is a neuropathology, albeit one about which our understanding is still rudimentary, and which is far from allowing schizophrenia to be diagnosable from a brain scan or down a microscope. Both neurons and glia are affected. Changes are prominent in, but not limited to, the prefrontal cortex and hippocampus. The neuropathology is likely to represent and reflect an altered connectivity and circuitry, caused at least partly by the susceptibility genes and mediated through a perturbation of brain development and synaptic plasticity.
Keywords
dementia; gliosis; morphometry; neurodevelopment; psychosis; synaptic plasticity
The most robust and important histological findings in schizophrenia are both negative. • The neuropathology of schizophrenia is not neurodegenerative. There are no discrete lesions such as neurofibrillary tangles, amyloid plaques, Lewy bodies, or other such features visible using a range of routine and immunocytochemical stains that would indicate the presence of any known neurodegenerative process. Importantly, this conclusion applies even to patients with schizophrenia with sufficiently severe cognitive impairment to warrant the label of dementia. The question of why patients with schizophrenia often have these deficits is, in neuropathological terms, entirely unexplained.2 • Second, contrary to some earlier claims, there is no gliosis (the proliferation and hypertrophy of astrocytes, the supporting cells of the brain) in schizophrenia.3 Gliosis is a sign of inflammation, injury, or other ongoing pathological processes. Hence the lack of gliosis is taken as a sign that the disorder is likely to be neurodevelopmental in origin, affecting mechanisms involved in the normal maturation of the brain. This interpretational issue is discussed below.
neurodegeneration;
Finding the neuropathology of schizophrenia has been one of the major quests of biological psychiatry for over 100 years. Indeed, Alzheimer wrote a paper on the subject in 1897, ten years before describing the disease that bears his name. However, although fundamental neuropathological discoveries were made in conditions such as Alzheimer’s disease and Pick’s disease, there was no such progress for schizophrenia. Both as a cause and a consequence of this failure, the field fell into neglect and disrepute for several decades, culminating in the infamous statement by the American neurologist Plum in 1972 that schizophrenia is ‘the graveyard of neuropathologists’. The situation has changed since then, however, and there is now compelling evidence for a neuropathology of schizophrenia, at least in the sense that there are structural differences robustly demonstrable in the brain of patients with the disorder, compared with normal subjects on a groupwise basis. On the other hand, the details and meaning of these changes are still tantalizingly elusive.
Morphometric and cytoarchitectural changes With these important possibilities ruled out, it has proved difficult to pin down what the positive histological changes are, although the findings can be grouped together as broadly cytoarchitectural in nature, that is, affecting the morphology and spatial organization of neurons and their processes (Table 2). As a rule, the more dramatic the initial finding – and the more it has permeated textbooks – the less robust it has proved to be. For example, dysplasia (disorganized, misplaced, and misshapen
Gross pathology The main impetus to contemporary neuropathological studies of schizophrenia came from structural brain imaging. Initially computed tomography, then magnetic resonance imaging (MRI) showed clearly that there are quantitative structural differences
Key structural imaging findings in schizophrenia • Enlarged lateral and third ventricles • Decreased brain volume • Decreased cortical volume, especially temporal lobes • Decreased hippocampal volume • Changes are present in first-episode subjects and, to some extent, in those at risk of the illness and in unaffected relatives
Paul J Harrison MA, DM (Oxon) FRCPsych is Professor and Honorary Consultant in Psychiatry at the University of Oxford, UK. He qualified in medicine from Oxford and trained in psychiatry and neuroscience in Oxford and Imperial College, London. His research interests centre upon the neurobiology, genetics, and psychopharmacology of schizophrenia. Conflicts of interest: none declared.
PSYCHIATRY 7:10
Table 1
421
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
micro-arrays to study gene expression systematically in schizophrenia have also found support for an involvement of synaptic and oligodendrocyte genes. Regarding the pathways and synapses involved, excitatory (glutamatergic) and sub-types of inhibitory (GABAergic) ones appear to be affected; there are surprisingly few alterations reported in dopaminergic pathways. The thalamus, a collection of nuclei that serve as the primary relay station to the cerebral cortex, is a further area of interest, especially the pulvinar and mediodorsal thalamic nuclei. Both have been found to be smaller, and to contain fewer neurons, in several studies of schizophrenia. The evidence for the pulvinar nuclei is particularly strong. The pulvinar projects mainly to the posterior parts of the cerebral cortex (the temporal and occipital association cortices), whereas the mediodorsal nucleus has extensive reciprocal connections with the prefrontal cortex. The origin of the thalamic decreases is not known, and could be either primary or secondary to alterations in the cerebral cortex and other interconnected regions. As to the regional distribution of the neuropathology, the main positive findings are in the hippocampus, prefrontal cortex, and thalamus. Although this is broadly consistent with the areas implicated by the MRI analyses, and with the neuropsychological deficits in cognition that occur in the disorder, it is also true that these are the regions wherein most studies have been carried out. Indeed, both the cerebellum and the visual cortex, regions until recently ignored in schizophrenia, are now known to exhibit structural as well as functional alterations in the disease.
Key neuropathological findings in schizophrenia Finding
Evidence
No neurodegenerative changes Decreased brain weight No gliosis Smaller thalamic nuclei with fewer neuronsa Smaller pyramidal neuronsb Decreased synaptic markers Dysfunctional cortical GABA interneuronsc Dysplasias in entorhinal cortexd Abnormal distribution of cortical white matter neurons Oligodendrocytes: reduced and/or hypofunctional Misalignment of hippocampal pyramidal neurons
+++++ +++++ ++++ +++ +++ +++ +++ ++ ++ ++ +/−
a
Especially pulvinar and mediodorsal nuclei. In neocortex (especially lamina III) and hippocampus. c Loss of staining for the GABAergic markers, notably the γ-aminobutyric acid (GABA) synthetic enzyme, glutamic acid decarboxylase 67 (GAD67), and the chandelier cell sub-type. d Especially the location of pre-alpha cell clusters in laminae II/III. b
Table 2
neurons) in the entorhinal cortex, which connects the hippocampus with the neocortex, was reported in 1986. Such a finding would be strongly suggestive of a prenatal developmental anomaly. However, subsequent studies have only partially replicated this observation.4 Similarly, a report that pyramidal neurons in the hippocampus were not aligned in their usual regular orientation (‘disarrayed’), also indicative of a developmental disturbance, has not been replicated independently. A third wellpublicized finding was an alteration in the distribution of neurons in the sub-cortical white matter, putatively the remnants of the sub-plate from which the cortex develops5; such alterations have been found in some, but not all, of the subsequent studies. A further influential finding was by Selemon and Goldman-Rakic,6 who in a series of studies found an increased packing density of neurons in the cerebral cortex. They interpreted this as reflecting a loss of the brain tissue surrounding the neurons, the neuropil, which comprises the dendrites and axons, as well as the glial and vascular elements of the brain, and proposed the ‘reduced neuropil’ hypothesis. Their findings contributed to the view of schizophrenia as a disorder of neural connections, mentioned below, but as yet the key observations remain to be confirmed.7 Several studies, including that of Selemon and Goldman-Rakic,6 have found a decreased size of pyramidal neurons. The size of a neuron is related to the volume of axon and dendrites which it has to support, and also to its activity. Thus, the finding of smaller neurons in schizophrenia suggests less extensive axonal and dendritic trees, and hence that the neurons may be making fewer or less active connections. Support for this interpretation comes from studies of synaptic and dendritic markers, which have been reasonably consistent in showing decreases in the same brain areas. Recent data showing reductions in the number and/or activity of oligodendrocytes are in keeping with this kind of interpretation,8 as these glial cells regulate the myelin sheaths that surround most axons, and contribute to synaptic homeostasis. Studies using
PSYCHIATRY 7:10
Is the pathology an artefact of medication? Virtually all patients included in contemporary neuropathological studies had received antipsychotic drugs (and other treatments) in life, raising the possibility that the findings might be caused by, or contributed to, or even partially reversed by, the medication. The evidence here is equivocal too. Certainly, there are reasons to be confident that not all of the effects are medication related – notably the fact that the MRI studies show decreased brain volumes to be present in first-episode and never-medicated subjects. In addition, few of the reported neuropathological findings correlate with the extent of antipsychotic exposure the subjects had received in life, and several experimental studies in rodents and monkeys do not reproduce similar findings. Overall, therefore, medication is probably an over-rated concern in this field.9 On the other hand, there are recent reports that monkeys chronically treated with antipsychotics (either haloperidol or olanzapine) do show smaller brain volumes, increased neuronal density, and decreased glial density, three findings seen in neuropathology.10 Furthermore, some longitudinal imaging studies in patients suggest changes associated with medication (although this is hard to disentangle from progressive alterations related to the disorder). Finally, there is agreement that typical antipsychotics do produce enlargement of the basal ganglia (caudate, putamen, globus pallidus), probably reflecting increased vascularity as well as synaptic plasticity.
Schizophrenia as a disorder of neural connectivity Assuming that the neuropathological findings relate, at least partly, to schizophrenia itself, the question becomes: ‘What do they tell us about the nature of the disorder?’. 422
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
In spite of the many gaps in knowledge, the neuronal and synaptic findings have been major contributors to the emerging consensus, mentioned above, that the neuropathology of schizophrenia is one of connectivity. In other words, the histological basis of the syndrome is a difference in the neural circuitry or wiring of the brain, manifested by differences in the morphology and organization of neurons. Both intrinsic (local) and extrinsic (long-range) connections may be affected; the latter include corticocortical, interhemispheric, and corticothalamic pathways. The nature of the ‘disconnectivity’ is not a simple lack, or gross misrouting, of connections, but more likely a subtle change in some more ‘fine-grained’ aspect, such as the precise structure or location of sub-populations of synaptic terminals and dendritic spines. This cytoarchitectural pathology is the anatomical counterpart of the aberrant functional connectivity apparent from positron emission tomography (PET) and functional MRI studies, and to the fragmentation of mental functioning in schizophrenia apparent to clinicians since Eugen Bleuler. If there is a structural basis to the pathophysiology of the syndrome, it would help explain why many of the cardinal features are trait rather than just state abnormalities, and perhaps why individuals are vulnerable to relapse, in that a ‘miswired’ brain may be less able to respond rapidly or fully to stressors and other environmental demands.
Some key unanswered questions • Is the neuropathology specific to schizophrenia? • Do different neuropathological findings map on to different features of schizophrenia? • When do changes occur, and how do they progress? • How is the neuropathology related to the dopamine abnormalities? • How much of the neuropathology is related to medication, and do different antipsychotics have differing effects? • How is the neuropathology related to the susceptibility genes? Table 3
(NMDA) sub-type of glutamate receptor).13 Although this seeming convergence of the genes’ functional roles may prove to be illusory, it is strikingly consistent with the pre-existing evidence and theories that the structure and function of synapses and the neural circuits in which they participate are key to the pathophysiology of the disorder. In this scenario, the cytoarchitectural features of schizophrenia are re-interpreted as being, at least partly, a manifestation of the genes that predispose – probably during neurodevelopment and by interacting with environmental factors – to the disorder.14 This would fit in with the fact that some of the imaging (and neuropsychological) features of the illness are also seen, in attenuated form, in unaffected relatives, who share some of the genetic predisposition. There is already evidence that the risk alleles in some of the genes do indeed affect brain structure as determined by MRI (e.g. Meyer-Lindenberg et al.15), but this has yet to be extended to post-mortem observations. Clarifying the relationship between genes and neuropathology has become a major new research focus in schizophrenia, and forms one of the most pressing questions in the field (Table 3).
Timing of the neuropathology: schizophrenia as a neurodevelopmental disorder When might the neuropathological changes have occurred? The lack of gliosis or other evidence of neurodegenerative change noted above is, by default, strong support for the view that schizophrenia is a disorder of early brain development.11,12 By inference, the alterations are present at, and probably before, the onset of psychotic symptoms. Although this is impossible to prove in a post-mortem study, it is supported by MRI and other findings in children and adolescents who later develop schizophrenia. However, it must be emphasized that there is as yet no unequivocal neuropathological evidence for the neurodevelopmental hypothesis (as would be provided by, for example, clear and consistent evidence of focal dysplasias). Several studies are now looking at specific molecules that are known to be important in brain maturation, in an effort to provide more direct support for the developmental view. The best evidence of this kind to date comes from the finding that the regulation and expression of reelin (a gene central to formation of neuronal connections) is abnormal in the disorder.
Conclusion
Neuropathology and the genetic basis of schizophrenia
Schizophrenia should no longer be viewed as a ‘functional’ disorder, lacking any structural involvement of the brain. There is a neuropathology, albeit one about which our understanding is still rudimentary, and which is far from allowing schizophrenia to be diagnosable from a brain scan or down a microscope. At present, the best guess is that the anatomical basis of the syndrome is an altered neuronal connectivity, caused at least partly by susceptibility genes and mediated through a perturbation of brain development and synaptic plasticity, and the responses of these processes to environmental experiences and exposures. ◆
A major breakthrough of the past few years has been the identification of susceptibility genes for schizophrenia. Although the evidence is far from complete, for several of the genes there is sufficient evidence to begin to consider their implications. One noteworthy feature is that the genes mostly code for proteins whose main functions involve synapses in one way or another, whether in terms of their formation, receptor composition, plasticity, or signalling properties. Moreover, there is an apparent preference for the genes to affect excitatory synapses (those using glutamate as a transmitter via the N-methyl-d-aspartic acid
References 1 Harrison PJ, Freemantle N, Geddes JR. Meta-analysis of brain weight in schizophrenia. Schizophr Res 2003; 64: 25–35. 2 Arnold SA, Trojanowski JQ. Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol (Berl) 1996; 92: 217–31. 3 Roberts GW, Harrison PJ. Gliosis and its implications for the disease process. In: Harrison PJ, Roberts GW, eds. The neuropathology of
PSYCHIATRY 7:10
423
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
schizophrenia. Progress and interpretation. Oxford: Oxford University Press, 2000. 4 Falkai P, Schneider-Axmann T, Honer WG. Entorhinal cortex prealpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality. Biol Psychiatry 2000; 47: 937–43. 5 Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 1993; 50: 178–87. 6 Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999; 45: 17–25. 7 Cullen TJ, Walker MA, Eastwood SL, Esiri MM, Harrison PJ, Crow TJ. Anomalies of asymmetry of pyramidal cell density and structure in dorsolateral prefrontal cortex in schizophrenia. Br J Psychiatry 2006; 188: 26–31. 8 Hof PR, Haroutunian V, Friedrich VL, et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003; 53: 1075–85. 9 Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res 1999; 40: 87–99. 10 Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 2007; 32: 1216–23. 11 Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995; 346: 552–57. 12 Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409–32. 13 Harrison PJ, West V. Six degrees of separation: on the prior probability that schizophrenia susceptibility genes converge upon synapses, glutamate, and NMDA receptors. Mol Psychiatry 2006; 11: 981–3. 14 Harrison PJ. Schizophrenia genes and neurodevelopment. Biol Psychiatry 2007; 61: 1119–20.
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15 Meyer-Lindenberg A, Straub RE, Lipska BK, et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 2007; 117: 672–82.
Further reading Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593–624. (A detailed review) Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68. (Reviews the evidence for schizophrenia genes and how they may influence the neuropathology and neurobiology of the disorder) Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–24. (Discusses the evidence for, and the possible basis of, deficits in cortical interneurons. The review illustrates the ways in which neuropathology, developmental biology, and molecular biology are being combined to try to elucidate the circuits affected in the disorder) Stephan KE, Baldeweg T, Friston K. Synaptic plasticity and disconnection in schizophrenia. Biol Psychiatry 2006; 59: 929–39. (Reviews how synaptic plasticity may be affected in, and important for, schizophrenia and its genetic basis)
Acknowledgements Research in the author’s laboratory is supported by grants from the Medical Research Council, Stanley Medical Research Institute, and Wellcome Trust, and an unrestricted educational grant from GlaxoSmithKline.
424
© 2008 Elsevier Ltd. All rights reserved.
Neuropathology of schizophrenia
in living patients (Table 1). Alterations are present in patients experiencing their first episode, and some also in at-risk subjects, indicating that there is a pathology that cannot be explained away as an artefact of chronic illness and that is in some way related to the disorder itself. A simple but informative measure is brain size, with brain volume being reduced by about 3–4% based upon meta-analyses of the MRI literature, and brain weight by a similar amount as measured at post-mortem examination.1 Neuropathological studies have sought to explain the smaller brain, and to attempt to localize and characterize the histological and cellular correlates of schizophrenia.
Paul J Harrison
Abstract
The neuropathology is not degenerative
It is no longer tenable to view schizophrenia as a ‘functional’ disorder, lacking any structural involvement of the brain. There is a neuropathology, albeit one about which our understanding is still rudimentary, and which is far from allowing schizophrenia to be diagnosable from a brain scan or down a microscope. Both neurons and glia are affected. Changes are prominent in, but not limited to, the prefrontal cortex and hippocampus. The neuropathology is likely to represent and reflect an altered connectivity and circuitry, caused at least partly by the susceptibility genes and mediated through a perturbation of brain development and synaptic plasticity.
Keywords
dementia; gliosis; morphometry; neurodevelopment; psychosis; synaptic plasticity
The most robust and important histological findings in schizophrenia are both negative. • The neuropathology of schizophrenia is not neurodegenerative. There are no discrete lesions such as neurofibrillary tangles, amyloid plaques, Lewy bodies, or other such features visible using a range of routine and immunocytochemical stains that would indicate the presence of any known neurodegenerative process. Importantly, this conclusion applies even to patients with schizophrenia with sufficiently severe cognitive impairment to warrant the label of dementia. The question of why patients with schizophrenia often have these deficits is, in neuropathological terms, entirely unexplained.2 • Second, contrary to some earlier claims, there is no gliosis (the proliferation and hypertrophy of astrocytes, the supporting cells of the brain) in schizophrenia.3 Gliosis is a sign of inflammation, injury, or other ongoing pathological processes. Hence the lack of gliosis is taken as a sign that the disorder is likely to be neurodevelopmental in origin, affecting mechanisms involved in the normal maturation of the brain. This interpretational issue is discussed below.
neurodegeneration;
Finding the neuropathology of schizophrenia has been one of the major quests of biological psychiatry for over 100 years. Indeed, Alzheimer wrote a paper on the subject in 1897, ten years before describing the disease that bears his name. However, although fundamental neuropathological discoveries were made in conditions such as Alzheimer’s disease and Pick’s disease, there was no such progress for schizophrenia. Both as a cause and a consequence of this failure, the field fell into neglect and disrepute for several decades, culminating in the infamous statement by the American neurologist Plum in 1972 that schizophrenia is ‘the graveyard of neuropathologists’. The situation has changed since then, however, and there is now compelling evidence for a neuropathology of schizophrenia, at least in the sense that there are structural differences robustly demonstrable in the brain of patients with the disorder, compared with normal subjects on a groupwise basis. On the other hand, the details and meaning of these changes are still tantalizingly elusive.
Morphometric and cytoarchitectural changes With these important possibilities ruled out, it has proved difficult to pin down what the positive histological changes are, although the findings can be grouped together as broadly cytoarchitectural in nature, that is, affecting the morphology and spatial organization of neurons and their processes (Table 2). As a rule, the more dramatic the initial finding – and the more it has permeated textbooks – the less robust it has proved to be. For example, dysplasia (disorganized, misplaced, and misshapen
Gross pathology The main impetus to contemporary neuropathological studies of schizophrenia came from structural brain imaging. Initially computed tomography, then magnetic resonance imaging (MRI) showed clearly that there are quantitative structural differences
Key structural imaging findings in schizophrenia • Enlarged lateral and third ventricles • Decreased brain volume • Decreased cortical volume, especially temporal lobes • Decreased hippocampal volume • Changes are present in first-episode subjects and, to some extent, in those at risk of the illness and in unaffected relatives
Paul J Harrison MA, DM (Oxon) FRCPsych is Professor and Honorary Consultant in Psychiatry at the University of Oxford, UK. He qualified in medicine from Oxford and trained in psychiatry and neuroscience in Oxford and Imperial College, London. His research interests centre upon the neurobiology, genetics, and psychopharmacology of schizophrenia. Conflicts of interest: none declared.
PSYCHIATRY 7:10
Table 1
421
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
micro-arrays to study gene expression systematically in schizophrenia have also found support for an involvement of synaptic and oligodendrocyte genes. Regarding the pathways and synapses involved, excitatory (glutamatergic) and sub-types of inhibitory (GABAergic) ones appear to be affected; there are surprisingly few alterations reported in dopaminergic pathways. The thalamus, a collection of nuclei that serve as the primary relay station to the cerebral cortex, is a further area of interest, especially the pulvinar and mediodorsal thalamic nuclei. Both have been found to be smaller, and to contain fewer neurons, in several studies of schizophrenia. The evidence for the pulvinar nuclei is particularly strong. The pulvinar projects mainly to the posterior parts of the cerebral cortex (the temporal and occipital association cortices), whereas the mediodorsal nucleus has extensive reciprocal connections with the prefrontal cortex. The origin of the thalamic decreases is not known, and could be either primary or secondary to alterations in the cerebral cortex and other interconnected regions. As to the regional distribution of the neuropathology, the main positive findings are in the hippocampus, prefrontal cortex, and thalamus. Although this is broadly consistent with the areas implicated by the MRI analyses, and with the neuropsychological deficits in cognition that occur in the disorder, it is also true that these are the regions wherein most studies have been carried out. Indeed, both the cerebellum and the visual cortex, regions until recently ignored in schizophrenia, are now known to exhibit structural as well as functional alterations in the disease.
Key neuropathological findings in schizophrenia Finding
Evidence
No neurodegenerative changes Decreased brain weight No gliosis Smaller thalamic nuclei with fewer neuronsa Smaller pyramidal neuronsb Decreased synaptic markers Dysfunctional cortical GABA interneuronsc Dysplasias in entorhinal cortexd Abnormal distribution of cortical white matter neurons Oligodendrocytes: reduced and/or hypofunctional Misalignment of hippocampal pyramidal neurons
+++++ +++++ ++++ +++ +++ +++ +++ ++ ++ ++ +/−
a
Especially pulvinar and mediodorsal nuclei. In neocortex (especially lamina III) and hippocampus. c Loss of staining for the GABAergic markers, notably the γ-aminobutyric acid (GABA) synthetic enzyme, glutamic acid decarboxylase 67 (GAD67), and the chandelier cell sub-type. d Especially the location of pre-alpha cell clusters in laminae II/III. b
Table 2
neurons) in the entorhinal cortex, which connects the hippocampus with the neocortex, was reported in 1986. Such a finding would be strongly suggestive of a prenatal developmental anomaly. However, subsequent studies have only partially replicated this observation.4 Similarly, a report that pyramidal neurons in the hippocampus were not aligned in their usual regular orientation (‘disarrayed’), also indicative of a developmental disturbance, has not been replicated independently. A third wellpublicized finding was an alteration in the distribution of neurons in the sub-cortical white matter, putatively the remnants of the sub-plate from which the cortex develops5; such alterations have been found in some, but not all, of the subsequent studies. A further influential finding was by Selemon and Goldman-Rakic,6 who in a series of studies found an increased packing density of neurons in the cerebral cortex. They interpreted this as reflecting a loss of the brain tissue surrounding the neurons, the neuropil, which comprises the dendrites and axons, as well as the glial and vascular elements of the brain, and proposed the ‘reduced neuropil’ hypothesis. Their findings contributed to the view of schizophrenia as a disorder of neural connections, mentioned below, but as yet the key observations remain to be confirmed.7 Several studies, including that of Selemon and Goldman-Rakic,6 have found a decreased size of pyramidal neurons. The size of a neuron is related to the volume of axon and dendrites which it has to support, and also to its activity. Thus, the finding of smaller neurons in schizophrenia suggests less extensive axonal and dendritic trees, and hence that the neurons may be making fewer or less active connections. Support for this interpretation comes from studies of synaptic and dendritic markers, which have been reasonably consistent in showing decreases in the same brain areas. Recent data showing reductions in the number and/or activity of oligodendrocytes are in keeping with this kind of interpretation,8 as these glial cells regulate the myelin sheaths that surround most axons, and contribute to synaptic homeostasis. Studies using
PSYCHIATRY 7:10
Is the pathology an artefact of medication? Virtually all patients included in contemporary neuropathological studies had received antipsychotic drugs (and other treatments) in life, raising the possibility that the findings might be caused by, or contributed to, or even partially reversed by, the medication. The evidence here is equivocal too. Certainly, there are reasons to be confident that not all of the effects are medication related – notably the fact that the MRI studies show decreased brain volumes to be present in first-episode and never-medicated subjects. In addition, few of the reported neuropathological findings correlate with the extent of antipsychotic exposure the subjects had received in life, and several experimental studies in rodents and monkeys do not reproduce similar findings. Overall, therefore, medication is probably an over-rated concern in this field.9 On the other hand, there are recent reports that monkeys chronically treated with antipsychotics (either haloperidol or olanzapine) do show smaller brain volumes, increased neuronal density, and decreased glial density, three findings seen in neuropathology.10 Furthermore, some longitudinal imaging studies in patients suggest changes associated with medication (although this is hard to disentangle from progressive alterations related to the disorder). Finally, there is agreement that typical antipsychotics do produce enlargement of the basal ganglia (caudate, putamen, globus pallidus), probably reflecting increased vascularity as well as synaptic plasticity.
Schizophrenia as a disorder of neural connectivity Assuming that the neuropathological findings relate, at least partly, to schizophrenia itself, the question becomes: ‘What do they tell us about the nature of the disorder?’. 422
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
In spite of the many gaps in knowledge, the neuronal and synaptic findings have been major contributors to the emerging consensus, mentioned above, that the neuropathology of schizophrenia is one of connectivity. In other words, the histological basis of the syndrome is a difference in the neural circuitry or wiring of the brain, manifested by differences in the morphology and organization of neurons. Both intrinsic (local) and extrinsic (long-range) connections may be affected; the latter include corticocortical, interhemispheric, and corticothalamic pathways. The nature of the ‘disconnectivity’ is not a simple lack, or gross misrouting, of connections, but more likely a subtle change in some more ‘fine-grained’ aspect, such as the precise structure or location of sub-populations of synaptic terminals and dendritic spines. This cytoarchitectural pathology is the anatomical counterpart of the aberrant functional connectivity apparent from positron emission tomography (PET) and functional MRI studies, and to the fragmentation of mental functioning in schizophrenia apparent to clinicians since Eugen Bleuler. If there is a structural basis to the pathophysiology of the syndrome, it would help explain why many of the cardinal features are trait rather than just state abnormalities, and perhaps why individuals are vulnerable to relapse, in that a ‘miswired’ brain may be less able to respond rapidly or fully to stressors and other environmental demands.
Some key unanswered questions • Is the neuropathology specific to schizophrenia? • Do different neuropathological findings map on to different features of schizophrenia? • When do changes occur, and how do they progress? • How is the neuropathology related to the dopamine abnormalities? • How much of the neuropathology is related to medication, and do different antipsychotics have differing effects? • How is the neuropathology related to the susceptibility genes? Table 3
(NMDA) sub-type of glutamate receptor).13 Although this seeming convergence of the genes’ functional roles may prove to be illusory, it is strikingly consistent with the pre-existing evidence and theories that the structure and function of synapses and the neural circuits in which they participate are key to the pathophysiology of the disorder. In this scenario, the cytoarchitectural features of schizophrenia are re-interpreted as being, at least partly, a manifestation of the genes that predispose – probably during neurodevelopment and by interacting with environmental factors – to the disorder.14 This would fit in with the fact that some of the imaging (and neuropsychological) features of the illness are also seen, in attenuated form, in unaffected relatives, who share some of the genetic predisposition. There is already evidence that the risk alleles in some of the genes do indeed affect brain structure as determined by MRI (e.g. Meyer-Lindenberg et al.15), but this has yet to be extended to post-mortem observations. Clarifying the relationship between genes and neuropathology has become a major new research focus in schizophrenia, and forms one of the most pressing questions in the field (Table 3).
Timing of the neuropathology: schizophrenia as a neurodevelopmental disorder When might the neuropathological changes have occurred? The lack of gliosis or other evidence of neurodegenerative change noted above is, by default, strong support for the view that schizophrenia is a disorder of early brain development.11,12 By inference, the alterations are present at, and probably before, the onset of psychotic symptoms. Although this is impossible to prove in a post-mortem study, it is supported by MRI and other findings in children and adolescents who later develop schizophrenia. However, it must be emphasized that there is as yet no unequivocal neuropathological evidence for the neurodevelopmental hypothesis (as would be provided by, for example, clear and consistent evidence of focal dysplasias). Several studies are now looking at specific molecules that are known to be important in brain maturation, in an effort to provide more direct support for the developmental view. The best evidence of this kind to date comes from the finding that the regulation and expression of reelin (a gene central to formation of neuronal connections) is abnormal in the disorder.
Conclusion
Neuropathology and the genetic basis of schizophrenia
Schizophrenia should no longer be viewed as a ‘functional’ disorder, lacking any structural involvement of the brain. There is a neuropathology, albeit one about which our understanding is still rudimentary, and which is far from allowing schizophrenia to be diagnosable from a brain scan or down a microscope. At present, the best guess is that the anatomical basis of the syndrome is an altered neuronal connectivity, caused at least partly by susceptibility genes and mediated through a perturbation of brain development and synaptic plasticity, and the responses of these processes to environmental experiences and exposures. ◆
A major breakthrough of the past few years has been the identification of susceptibility genes for schizophrenia. Although the evidence is far from complete, for several of the genes there is sufficient evidence to begin to consider their implications. One noteworthy feature is that the genes mostly code for proteins whose main functions involve synapses in one way or another, whether in terms of their formation, receptor composition, plasticity, or signalling properties. Moreover, there is an apparent preference for the genes to affect excitatory synapses (those using glutamate as a transmitter via the N-methyl-d-aspartic acid
References 1 Harrison PJ, Freemantle N, Geddes JR. Meta-analysis of brain weight in schizophrenia. Schizophr Res 2003; 64: 25–35. 2 Arnold SA, Trojanowski JQ. Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol (Berl) 1996; 92: 217–31. 3 Roberts GW, Harrison PJ. Gliosis and its implications for the disease process. In: Harrison PJ, Roberts GW, eds. The neuropathology of
PSYCHIATRY 7:10
423
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
schizophrenia. Progress and interpretation. Oxford: Oxford University Press, 2000. 4 Falkai P, Schneider-Axmann T, Honer WG. Entorhinal cortex prealpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality. Biol Psychiatry 2000; 47: 937–43. 5 Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 1993; 50: 178–87. 6 Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999; 45: 17–25. 7 Cullen TJ, Walker MA, Eastwood SL, Esiri MM, Harrison PJ, Crow TJ. Anomalies of asymmetry of pyramidal cell density and structure in dorsolateral prefrontal cortex in schizophrenia. Br J Psychiatry 2006; 188: 26–31. 8 Hof PR, Haroutunian V, Friedrich VL, et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003; 53: 1075–85. 9 Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res 1999; 40: 87–99. 10 Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 2007; 32: 1216–23. 11 Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995; 346: 552–57. 12 Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409–32. 13 Harrison PJ, West V. Six degrees of separation: on the prior probability that schizophrenia susceptibility genes converge upon synapses, glutamate, and NMDA receptors. Mol Psychiatry 2006; 11: 981–3. 14 Harrison PJ. Schizophrenia genes and neurodevelopment. Biol Psychiatry 2007; 61: 1119–20.
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15 Meyer-Lindenberg A, Straub RE, Lipska BK, et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 2007; 117: 672–82.
Further reading Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593–624. (A detailed review) Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68. (Reviews the evidence for schizophrenia genes and how they may influence the neuropathology and neurobiology of the disorder) Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–24. (Discusses the evidence for, and the possible basis of, deficits in cortical interneurons. The review illustrates the ways in which neuropathology, developmental biology, and molecular biology are being combined to try to elucidate the circuits affected in the disorder) Stephan KE, Baldeweg T, Friston K. Synaptic plasticity and disconnection in schizophrenia. Biol Psychiatry 2006; 59: 929–39. (Reviews how synaptic plasticity may be affected in, and important for, schizophrenia and its genetic basis)
Acknowledgements Research in the author’s laboratory is supported by grants from the Medical Research Council, Stanley Medical Research Institute, and Wellcome Trust, and an unrestricted educational grant from GlaxoSmithKline.
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