Schizophrenia, Biological Mechanisms of
Nora I. Perrone-Bizzozero and W. Michael Bullock, Department of Neurosciences, University of New Mexico School of Medicine.
Schizophrenia is a chronic and severely debilitating mental disorder that affects approximately 1 % of the world's population. Although schizophrenia has been recognized for over 100 years, the causes and pathophysiological mechanisms of this illness remained rather elusive until recently. Evidence obtained during the last 3 decades suggests that schizophrenia is a neurodevelopmental disorder that affects the structure and function of distributed brain regions. Multiple neurotransmitter systems have been implicated, as have both gray and white matter abnormalities. These structural alterations result in synaptic miscommunication at local neuronal circuits and long-distance functional disconnectivity, with both genetic and environmental factors contributing to these deficits. This article will discuss our current understanding of the biological and neurochemical bases of schizophrenia and will describe new pharmacological, genetic, and lesion models used for testing the mechanisms that underlie this devastating disease.
Schizophrenia was first identified in 1893 by the German psychiatrist Emil Kraepelin, who termed the disorder dementia praecox because of its early onset and irreversible mental decline. Then, 15 years later, the Swiss psychiatrist Eugen Bleuler recognized that the illness affected both the judgment and emotional state of the patient and referred to this disorder as schizophrenia, from the Greek schiz- to split and phren- mind. Bleuler identified the cardinal symptoms of the illness as loosening of associations, flat affect, social withdrawal, and ambivalence, and these criteria are still used for diagnostic purposes today. The onset of symptoms characteristically occurs during late adolescence and early adulthood. According to the Diagnostic and Statistical Manual IV (American Psychiatric Association, 1994), symptoms are categorized as positive or negative, and patients manifest these symptoms at various degrees during the course of their illness. Positive symptoms are manifestations of psychosis and include unusual behaviors such as paranoid or bizarre delusions, auditory hallucinations, and disorganized speech and thinking. In contrast, negative symptoms represent a loss of normal behaviors such as flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), and lack of motivation (avolition). In addition, patients exhibit unremitting cognitive deficits. The clinical course and outcome of schizophrenia shows great variability; however, typically, positive symptoms fluctuate and negative symptoms remain more stable over time.
Alterations in Brain Structure and Function
Unlike neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, the brains of patients with schizophrenia reveal neither gross anatomical changes nor the presence of pathological structures such as amyloid plaques or Lewy bodies. Thus, for much of the 1900s, psychiatry textbooks classified schizophrenia as a “functional” psychosis, for example, a condition that had no underlying physical brain disease. The technological advances in the past 25 years made it possible for investigators to re-evaluate the biological bases of schizophrenia systematically and provided evidence of subtle but consistent neuropathological and molecular alterations. Although most of these studies focused on the dorsolateral prefrontal cortex (DLPFC) and hippocampus, other brain regions including the thalamus, cerebellum, and its connecting white matter tracts have been implicated in schizophrenia (Fig. 1).
Figure 1. Schizophrenia affects the structure and function of distributed brain regions. Multiple brain regions are affected in schizophrenia including the dorsolateral prefrontal cortex, anterior cingulate gyrus, thalamus hippocampus/entorhinal cortex, and cerebellum. Arrows show the cortico-cerebellar-thalamic-cortical circuit, one of the networks implicated in schizophrenia (22).
Prefrontal cortex and anterior cingulate gyrus
Both postmortem tissue and neuroimaging analyses of the brain of patients with schizophrenia show small but reproducible gray matter reductions. In the prefrontal cortex (PFC), these changes were shown to be related to decreases in neuronal cell size and neuropil volume but not to a reduction in cell numbers (1). In the PFC, lamina-specific reductions in dendritic spine density were observed in the layer III pyramidal neurons (2) (Fig. 2). Because these cells play a critical role in cortical-cortical communications between adjacent and distant regions of the neocortex, a reduction in spine density suggests an impaired connectivity of the prefrontal cortex in the patients. Supporting this idea, the levels of the synaptic protein synaptophysin were shown to decrease in the PFC of patients along with increases in the growth-associated protein GAP-43, a marker of immature and/or “plastic” synapses (3, 4). The ratio of synaptophysin to GAP-43 is considered a putative index of synaptic maturation. Therefore, it is likely that this process is impaired in schizophrenia. Interestingly, GAP-43 mRNA levels were shown to be decreased in the PFC (5), which suggests that the observed increases in GAP-43 protein may be restricted to projections coming from other cortical and subcortical brain regions. In agreement with these structural and molecular alterations, patients with schizophrenia show signs of “hypofrontality,” which is characterized by working memory deficits and decreased cerebral blood flow in the frontal lobe (6, 7).
An altered distribution of neurons and axons was also seen in the anterior cingulate gyrus (8). Both within the prefrontal cortex and the anterior cingulate gyrus, the number of specific subtypes of inhibitory gamma-amino butyric acid (GABA) interneurons, such as the basket cells and chandelier neurons depicted in Fig. 2, was found to be decreased (9). In contrast, an increased number of interstitial white matter neurons were found in deep layers of the prefrontal cortex and other brain regions (10), which suggests the possibility of neuronal migration defects in schizophrenia.
Figure 2. Neurochemical and morphological alterations in the prefrontal cortex of patients with schizophrenia. The diagram shows some of the cell types in the layers I—VI of the dorsolateral prefrontal cortex, including glutamatergic pyramidal neurons (light gray) and GABAergic somatostatin-containing neurons, basket/wide arbor neurons and chandelier interneurons (dark gray), along with the changes in cell structure, gene expression, and neurotransmission observed in this region. These changes include decreased mRNA levels for several markers of GABAergic interneurons and reductions in the GAT-1 GABA transporter immunoreactivity in axon cartridges from chandelier cells with increased levels of postsynaptic GABAA receptors in pyramidal cells. Adapted from Ref. 9 and other references in the text.
Convergent evidence from neuroimaging and neuropathological studies indicates that the structure and function of the hippocampus is compromised in schizophrenia. Patients with schizophrenia have decreased hippocampal volume (11, 12) and several cytoarchitectural abnormalities in both the hippocampus proper and entorhinal cortex (13). In addition, neuropathological examination of postmortem hippocampal tissue revealed a decreased number of GABAergic interneurons and several synaptic protein deficits in patients with schizophrenia (14-16). In contrast to the PFC, the levels of GAP-43 protein and the ratio of GAP-43 to synaptophysin mRNAs was decreased in the hippocampus of patients with schizophrenia (16, 17). These changes were correlated with decreased levels of another marker of excitatory synapses, the synaptic protein complexin II (18). Along with these structural and molecular alterations, patients with schizophrenia exhibit reduced activation of the hippocampus during the encoding and retrieval of episodic and relational information, two well-characterized hippocampal dependent tasks (19-21).
Cerebellum and thalamus
Traditionally, most research performed in the field of schizophrenia has focused on brain regions directly implicated in the symptomatology of the disease, namely the PFC and limbic areas. Work by Andreasen et al. (22) first implicated the cerebellum as an affected structure in schizophrenia through the cortico-cerebellar-thalamic-cortical circuit (CCTCC, see arrows in Fig. 1). Dysfunction in one area of this circuit such as the thalamus (23) is thought to affect all other areas of the circuit. As a component of the CCTCC, the lateral hemispheres of the cerebellum have been implicated in cognitive and emotional functioning (24). Retroviral tracing and neuroimaging studies demonstrated cerebellar-prefrontal connections (25), which may contribute to cognitive dysfunction in schizophrenia. Intrinsic to these connections, a forward modeling system of the cerebellum has been proposed in which information from the motor cortex or the PFC is transferred to the cerebellum, and the cerebellum acts as a predictor of the outcome for both motor and cognitive functioning (26). Clinically, patients exhibit cerebellar neurological signs (27), deficits in eyeblink conditioning (28), and shortfalls in response timing (29). Neuroimaging studies have shown increases in blood flow and in glucose consumption in the cerebellum of schizophrenic patients relative to that of other brain regions (7, 30-32). In accordance with increased cerebellar activity, a recent study found that the levels of GAP-43 and brain-derived neurotrophic factor (BDNF), which are expressed in cerebellar granule cells in an activity-dependent manner, are upregulated in the patients (33). Additional molecular studies have shown decreased expression of the developmental marker reelin and the GABA synthesizing enzymes GAD65 and GAD67 and increases in the axonal chemorepellant protein semaphorin 3A (34-37). This finding is interesting considering the fact that GABA dysfunction in the cerebellum may lead to increases in granule cell firing and thus account for the increases seen in blood flow, glucose use, and the expression of activity-dependent genes. These changes ultimately could impact cerebellar contributions to cognitive (and motor) functioning in the patients.
White matter alterations
As described above and shown in Fig. 1, schizophrenia pathology is not restricted to a single brain region but affects multiple distributed areas. Brain regions considered important in the pathology of schizophrenia, such as the prefrontal cortex and temporal lobe, are linked normally to one another by tracts of dense and reciprocally afferent white matter, which thus suggests that white matter alterations could have a role in schizophrenia pathophysiology. Supporting this idea, white matter volume reductions have been reported in patients with schizophrenia (38-40). Analysis of frontal lobe white matter and corpus callosum of patients with diffusion tensor imaging revealed specific alterations in myelin structure (41). These changes were also observed in children and adolescent with schizophrenia (42), which indicates that white matter abnormalities may be present early in the disease. Postmortem tissue analysis at the light and electron microscopic levels also demonstrated the presence of myelin and oligodendrocyte abnormalities in schizophrenia (43-45). Along with these morphological abnormalities, microarray analysis of PFC tissue from subjects with schizophrenia also demonstrated downregulation of myelin-related and oligodendrocyte-related genes in the patients (46, 47). Finally, recent genetic studies identified polymorphisms in two important regulators of myelination, the transcription factor OLIG2 and the RNA-binding protein QKI, which are associated with increased risk for schizophrenia (48, 49).
Neurodevelopmental Hypothesis of Schizophrenia
As described above, the brains of patients with schizophrenia show alterations in the levels of the developmental markers reelin, GAP-43, and semaphorin 3A. In addition, evidence of disrupted neuronal distribution was found in several cortical areas and the hippocampal formation. These findings together with the absence of neuronal cell loss and concomitant reactive gliosis in these brain regions, both hallmarks of neurodegenerative disorders, led investigators to propose the neurodevelopmental hypothesis of schizophrenia (6, 50), which is still the prevailing theory in this disorder (51, 52). This hypothesis states that the illness is related to abnormal brain development and is supported by several pieces of evidence, including increased frequency of obstetric complications, viral infections, and other developmental stressors in patients with schizophrenia (see the sections below titled “Genetic and Environmental Factors” and “Developmental Models”) and the presence of soft neurological signs, cognitive impairment, and behavioral dysfunction in children long before the first psychotic episode.
As described in the previous sections, neuropathological studies demonstrated alterations in the levels of several synaptic proteins in the PFC, hippocampus, and cerebellum of patients with schizophrenia (13, 15, 53). These observations have lead to the hypothesis that the clinical symptoms of schizophrenia are manifestations of abnormal neural circuitry and dysfunctional communication between different brain regions (22, 51). These abnormalities affect multiple neurotransmitter systems. Although dopamine dysfunction in schizophrenia is widely accepted, a growing body of evidence suggests the involvement of glutamate, GABA, and other neurotransmitters in schizophrenia.
The discovery that the first antipsychotic drugs in the early 1950s, such as chlorpromazine, work in vitro by blocking dopamine receptors led to the hypothesis that schizophrenia was the result of excessive dopaminergic neurotransmission (54, 55). Supporting this hypothesis, drugs that enhance dopamine action (e.g., cocaine, amphetamines, and L-DOPA) worsen the symptoms of schizophrenia. However, it is clear that 1) not all patients respond to neuroleptic treatment and 2) not all symptoms are reversed by the medication.
Classical treatments for schizophrenia involve the administration of typical antipsychotics, such as haloperidol and chlorpromazine, which primarily bind to dopamine D2 receptors with high affinity, and atypical antipsychotics, such as clozapine and risperidone, which bind to a broader range of receptors including serotonergic and noradrenergic receptors among others. Although antipsychotics are effective at relieving the positive symptoms via their actions on D2 receptors, they are not effective in ameliorating the negative and cognitive symptoms. Interestingly, recent studies suggest that patients with schizophrenia may have hypofunctional D1 dopamine receptors in the prefrontal cortex (Fig. 2) and that agonists to this subtype of receptor may be effective in treating the working memory deficits associated with this illness (56, 57). In addition to drugs that work on monoamine receptors, new drugs that target glutamate, GABA, and cholinergic receptors are now being tested for ameliorating the cognitive dysfunction in schizophrenia (58, 59).
The glutamate hypothesis of schizophrenia was derived from the fact that drugs that block the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, such as phencyclidine (PCP) and ketamine, cause schizophrenia-like symptoms in humans and animal models. Furthermore, these drugs mimic not only the positive (psychotic) but also the negative and cognitive symptoms of the disease, which suggests that they act on the same basic pathophysiological mechanisms that are affected in schizophrenia.
NMDA receptor dysfunction has been characterized in different brain regions of patients with schizophrenia. Neuropathological studies revealed altered expression of receptor subunits in the prefrontal cortex (60), and single positron emission tomography studies have shown decreased NMDA receptor binding in the hippocampus of patients (61). Studies using NMDA receptor antagonists such as PCP, ketamine, and MK-801 additionally implicate hypofunction of these channels in schizophrenia (62). NMDA receptor antagonists have been shown to block NMDA channels located on GABAergic interneurons selectively (63, 64), which suggests that NMDA receptor dysfunction in a specific subset of these interneurons may be central to schizophrenia (62, 65).
GABA is the main inhibitory neurotransmitter in the brain, and dysfunction in certain subsets of GABAergic interneurons is one of the most consistent findings in the study of schizophrenia (9, 37, 66-68). Reductions in mRNA and protein levels of the 67 kD form of glutamic acid decarboxylase (GAD67), one of the GABA synthesizing enzymes, have been observed in the prefrontal cortex (69-71), the hippocampus (53, 72), the cerebellum (34, 35, 37), and other brain regions (73). As shown in Fig. 2, chandelier and basket interneurons in the PFC show decreased mRNA levels for the GAT-1 GABA transporter (74) and the calcium-binding protein parvalbumin (70), whereas other subtypes of interneurons have reduced levels of somatostastin (SST) mRNA (73). Postsynaptic changes such as increases in GABAA α2 receptor density and GABAA receptor radioligand binding in the PFC and anterior cingulate cortex were also observed (75-77). In addition to these findings, single nucleotide polymorphisms in the promoter region of the GAD67 gene were shown to be associated with reductions in gray matter in patients with childhood-onset schizophrenia (78). Considering the role of GABAergic interneurons in the modulation of excitatory output, it can be hypothesized that dysfunction in these cells may mediate some positive, negative, and cognitive symptoms seen in schizophrenia (79).
Other neurotransmitters: acetylcholine
Evidence of the involvement of acetylcholine in the pathophysiology of schizophrenia comes not only from the findings of decreased availability of cholinergic muscarinic receptors in patients (80, 81) but also from genetic studies that link specific polymorphisms in the gene for the alpha 7 nicotinic receptor (CHRNA7) with this illness. The CHRNA7 receptor is one of the ligand-gated ion channels that mediate fast cholinergic transmission at synapses. The CHRNA7 gene is located at chromosome 15q13-14, a locus implicated in the genetic transmission of schizophrenia (82, 83). Specific polymorphisms in CHRNA7 promoter region were shown to correlate with sensory gating alterations in patients with schizophrenia as measured by the P50 inhibition in auditory evoked response (84, 85). Furthermore, a recent study demonstrated that two additional single nucleotide polymorphisms (SNPs) in the CHRNA7 gene correlate with patterns of brain activation in schizophrenia patients during an auditory oddball task (86). The same study also linked an SNP in the gene coding for choline acetyltransferase, the acetylcholine synthesizing enzyme, with these abnormalities.
Genetic and Environmental Factors
Although the etiology of schizophrenia is not completely understood, it is becoming apparent that schizophrenia is a neurodevelopmental disorder that involves both genetic and environmental risk factors. The contribution of genetic factors was demonstrated by twin (87) and adoption studies (88) and by the higher prevalence of schizophrenia-like personality disorders in relatives of patients with schizophrenia (89). Other factors such as season of birth (90) and prenatal or perinatal complications such as ischemia (91) and viral infections (92) have also been identified as risk factors, although to a much lesser degree.
The influence of genetic factors is evidenced by the findings that about 50-75% of monozygotic twins with schizophrenia will have an affected twin and approximately 10% of first-degree relatives are also affected (93). Several genes have been associated with increased vulnerability for schizophrenia, including those encoding proteins associated with NMDA receptor function, synaptic plasticity, mitochondria energy metabolism, oxidative stress, development, and myelination (94, 95). Recent studies demonstrate that specific polymorphisms in some of these genes correlate with cognitive and neuroimaging abnormalities in patients (96). The best example of these polymorphisms is an SNP coding for the substitution of a valine for a methionine in position 108 of the short form (158 in long form) of the catechol-O-methyltransferase (COMT, Val 108/158 Met SNP) protein. The amino acid substitution results in a protein that has increased stability and, thus, increased rate of dopamine inactivation (97). This polymorphism has been associated with impaired performance in working memory tests and abnormal patterns of prefrontal cortex activation in both patients with schizophrenia and healthy volunteers (98). In addition, polymorphisms in the genes for BDNF and the metabotropic glutamate receptor 3 (GRM3), among others, have been associated with subtle but consistent alterations in PFC and hippocampal structure and function (96).
Schizophrenia is a purely human disease, which makes it hard to model the behavioral manifestations of this illness in animals. Nonetheless, animal models have been shown to reproduce specific aspects of the illness such as its effects on brain structure and function. Currently, several animal models are available to investigators. These animal models can be classified as developmental, pharmacological, genetic, and lesion models. Examples of these animal models are described below, and a complete listing of current animal models can be found in a recent review (99).
Given the evidence of perinatal stressors in some patients with schizophrenia, animal models have been generated to examine the influence of these factors in adult behavior. These studies demonstrated that animals exposed to prenatal viral infections, maternal deprivation, and other stressors exhibit several behavioral abnormalities consistent with schizophrenia, including disrupted prepulse inhibition, enhanced response to amphetamine, and impaired social interactions (100-102). Furthermore, some models show molecular and morphological deficits in the neocortex and hippocampus that mimic the alterations seen in patients with schizophrenia (103).
Pharmacological models that exploit the GABA/glutamate system have proven useful in studying the underlying pathophysiology of schizophrenia. These models include the picrotoxin-induced antagonism of GABAA receptors in rats (104) and the antagonism of NMDA receptors in both rodents and nonhuman primates (105-109). All these models affect the GABA/glutamate balance in different ways, but only the phencyclidine model has shown both the GABAergic and NMDA receptor changes seen in patients with schizophrenia (108, 110, 111).
Because PCP administration leads to many symptoms inherent to schizophrenia, studies are now being conducted that administer the compound to rodents and primates to induce a schizophrenic-like phenotype (106, 112). Acute and chronic dosing regimens show differential and often opposing effects in rodents. Immediately after administration of PCP to rats, neurons of the medial PFC show an initial excitation as seen by activation of early immediate genes (113). This effect is likely because of the preferential blockage of receptors in GABAergic interneurons by PCP and other NMDA receptor antagonists (64). This initial activation then is followed by a period of cortical depression as described by glucose use studies (114), presumably as a compensatory mechanism. Acute PCP administration also produces schizophrenia-like symptoms including social withdrawal (115), impaired sensory motor gating (116), and cognitive dysfunction (105, 107). Chronic intermittent exposure to low dose of PCP in rodents results in decreased metabolic activity in the prefrontal cortex, auditory cortex, hippocampus, and reticular nucleus of the thalamus (109), all regions affected in schizophrenia. Along with this decrease in metabolic function, decreases in parvalbumin expression were also seen (109), which mirror the chandelier and basket cell dysfunction seen in the prefrontal cortex of patients with schizophrenia (70). Taken together, the data suggest that the chronic intermittent PCP exposure model is one of the most functionally and neurochemically relevant animal models of unremitting schizophrenia.
Like the pharmacological model presented above, a genetic model also targets the NMDA receptor. This model was created by knocking down the NR1 subunit of the NMDA receptor, which is obligatory for receptor function, in mice so that only 5% of the protein is expressed (117). These animals, also known as NR1 hypomorphs, show NMDA receptor hypofunction and display several schizophrenia-like behaviors, such as reduced social interactions, increased locomotion, stereotypic movements, and sensorimotor gating deficits (117, 118). Interestingly, treatment of these mice with the atypical antipsychotic clozapine ameliorates some of these abnormal behaviors (117). Finally, similarly to schizophrenic patients, NR1 deficient mice show decreased metabolism in the medial prefrontal and anterior cingulate cortices (119).
Another well-characterized genetic model of schizophrenia consists of mice with target mutations in the Disrupted-inSchizophrenia 1 (DISC1) gene. This gene was discovered in a Scottish family with a high incidence of mental illness, including schizophrenia (120), which has a balanced translocation in this chromosome 1q42.1 locus. This protein is known to be critical for normal development (121), and mice that express mutant DISC1 protein exhibit brain and behavioral abnormalities suggestive of schizophrenia, such as impaired learning and memory processes and altered neuronal development (122-125).
Although no clear indication of a brain lesion is found in schizophrenia, developmental lesion models, such as the neonatal ventral hippocampal lesion (NVHL) and the neonatal amygdala lesion models, have been shown to reproduce several aspects of this illness (126, 127). For example, NVHL rats exhibit increased responses to dopamine agonists and NMDA receptor antagonists, which are manifested only after puberty. These animals also show impaired social interactions, altered sensorimotor gating, and cognitive deficits (128). At the molecular level, these animals show decreased numbers of GAD67 expressing interneurons in the medial PFC, which is similar to the findings observed in patients (71). Overall, this model also reproduces multiple aspects of schizophrenia behavior and pathophysiology.
In summary, the work reviewed in the previous sections suggests that schizophrenia is a neurodevelopmental disorder that affects the structure and function of distributed brain regions and their connecting white matter, with both genetic and environmental factors contributing to these alterations. As shown in Fig. 1, affected regions include frontal lobe and limbic system structures involved in cognition and emotion and areas that participate in sensorimotor integration such as the thalamus and cerebellum. Structural and molecular abnormalities in these regions result in synaptic alterations at local neuronal circuits and long-distance functional disconnectivity. Besides dopamine, multiple neurotransmitter systems have been implicated including glutamate, GABA, and acetylcholine. Based on these findings, drugs targeting specific subtypes of these receptors are now being tested in animal models and patients. It is expected that these new developments will help researchers not only to understand the etiology and basic pathophysiological mechanisms that lead to schizophrenia but also to develop better treatment strategies for this devastating illness.
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