SCHIZOPHRENIA

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Psychiatric Clinics of North AmericaVolume 21 • Number 1 • March 1998Copyright © 1998 W. B. Saunders Company

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SCHIZOPHRENIA

THE NEUROANATOMY AND NEUROCHEMISTRY OF SCHIZOPHRENIA

Cynthia Shannon Weickert, PhD Joel E. Kleinman, MD, PhD

From the Section of Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Program, National Institute of Mental Health Neuroscience Center at St. Elizabeths, Washington, District of Columbia

Although schizophrenia has been referred to as "the graveyard of neuropathologists," [133] this quip was not meant to discourage neuropathologic research on schizophrenia. Placed in its proper context, when Plum actually suggests is that this approach might be more successful if newer techniques were used to study schizophrenia. There are a number of newer approaches that have been used over the last 30 years, which have already led to some success or hold considerable promise in the future. In vivo neuroimaging and neuropsychologic testing are two examples of the former; molecular biology may represent the latter. Before we review the recent successes in neuroimaging and neuropsychology and the molecular biology of the future, it may be useful to see how neuroscience has led to progress in understanding the neuropathology of another brain disease leading to improved treatments.

Parkinson's Disease (PD) is a prototypical brain disease whose neurochemical deficits were first discovered by Ehringer and Hornykiewicz [54] leading to a major advance in treatment involving the use of a metabolic precursor, L-dopa, to reverse many of the motor symptoms. [41] Several misconceptions about PD may be worth noting so that we will not repeat these mistakes in our quest to understand other brain diseases such as schizophrenia. The first misconception is that PD is a disease, when in point of fact it is a syndrome, not a disease, with four symptoms

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(resting tremor, cogwheel rigidity, bradykinesia, and postural instability), not all of which are present in every case. [140] Because it is a syndrome, it may have a number of different causes, such as infection (postencephalitic), trauma (dementia pugilistica), toxin (N-methyl-4-phenyltetrahydropyridine, MPTP) or, as is the case with the majority of the patients, idiopathic. [140] If one realizes that PD is really a syndrome with multiple causes most of which are unknown, then it begins to sound a lot more like schizophrenia.

Second, the neurochemical pathology in PD is not confined to a loss of dopamine from the pars compacta of the substantia nigra, but instead, involves a loss of dopamine from a number of brain regions as well as a loss of norepinepherine from the locus coeruleus, a loss of serotonin from raphe neurons, and cholinergic deficits in the nucleus basalis of Meynert. [86] The so-called pathognomonic lesion in the substantia nigra is shared with at least five related neurologic disorders including striatal-nigral degeneration, the Shy-Drager syndrome, olivopontine cerebellar degeneration, Parkinson's Disease with motor neuron disease and spino-cerebellar nigral degeneration. [140] In so far as a prototypical neurologic disorder, such as PD, has such diverse neuropathology without a single pathognomonic lesion, a search for such a lesion in schizophrenia may represent a hopeless search for the Holy Grail.

Perhaps the more relevant question is how has neuropathology advanced our understanding of PD? The answer may well be that in Parkinson's Disease there is a visible lesion, a loss of pigment in the pars compacta of the substantia nigra (and the locus coerulus) that strongly directed the neurochemical research studies. After all, not knowing where to look makes even a MRI or PET scan fall short in the face of approximately 50 billion neurons with 1000 to 10,000 connections per neuron. In 1998, do we have enough clues to know where to look in the brains of schizophrenic patients? Three types of research suggest that at least three brain regions are involved in the neuropathology of schizophrenia.

Address reprint requests toCynthia Shannon Weickert, PhD

NIMH Neuroscience Center at St. Elizabeths2700 Martin Luther King, Jr, Avenue SEWashington, DC 20032

THE STRIATUM AND THE NUCLEUS ACCUMBENS

The first clue is a pharmacologic one involving the psychotic symptoms that characterize schizophrenia (hallucinations, delusions, and thought disorder). These symptoms are diminished or removed in the presence of dopamine type II (D-2) receptor blockers. There is a striking correlation between D-2 receptor blockade and antipsychotic efficacy of a number of drugs. [43] [144] Although this correlation is not perfect (i.e., clozapine being the most striking exception) there has yet to be a better neurochemical mechanism to explain the efficacy of most antipsychotics. Even the exception, clozapine, still has substantial D-2 receptor blocking capacity. [43] [144] D-2 receptors are present in such large numbers in the striatum/nucleus accumbens in the human brain that they have been visualized in vivo with PET and SPECT scans. [42] [56] [57] [76] [114] [173] [174] As a consequence the striatum/nucleus accumbens has become one practical

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choice to focus neuropathologic efforts. That is not to say that there are not D-2 receptors elsewhere. However, with the exception of the anterior pituitary gland (which is outside the brain per se), the D-2 receptors in substantia nigra, globus pallidus, and cerebral cortex are sufficiently less dense so that they have not been visualized on PET and SPECT scans. [42] [56] [57] [76] [114] [173] [174] Difficulties in measuring these receptors, in areas other than the dorsal and ventral striatum, have made them less attractive to researchers, but they cannot as yet be excluded as possible loci for the antipsychotic efficacy of neuroleptics. Lastly, of the three major sites (caudate, putamen, and nucleus accumbens), the latter attracts the most attention because of its extensive connections to the limbic system (i.e., inputs from the amygdala/hippocampus/entorhinal cortex). [122]

The most consistent postmortem neurochemical abnormality in the brains of schizophrenic patients involves increases in D-2 receptor numbers in the striatum/nucleus accumbens. * Unfortunately, this finding may turn out to be a result of prior neuroleptic treatment rather than a primary cause of psychotic symptoms in schizophrenic patients.36b [103] In vivo neuroimaging studies of drug-naive schizophrenic patients have with one exception [174] not found increases in D-2 receptors in the striatum/nucleus accumbens. [56] [57] [76] [114] There have been no clear replicable structural or neurochemical abnormalities, including other dopamine receptors, in the striatum/nucleus accumbens. [16] Although it has not been that fruitful thus far, the weight of the initial pharmacologic clue (that antipsychotic efficacy is related to D-2 receptor blockade) makes the nucleus accumbens and its limbic connections remain as important potential loci for the neuropathology of schizophrenia.

HIPPOCAMPUS AND THE ENTORHINAL CORTEX

More than 100 computed tomographic or MRI studies have found enlarged ventricles in patients with schizophrenia. This finding does not appear to be secondary to neuroleptic treatment, [150] nor is it progressive as one might expect with atrophy. [1] [80] [156] The results of a meta analysis of neuroimaging studies suggest that although the increases may be subtle, they may exist throughout the schizophrenic patient population. [47] A MRI study of identical twins discordant for schizophrenia confirms this hypothesis in so far as schizophrenic patients with normal ventricle size appear to have larger ventricles than their healthy identical twins. [159] Enlarged ventricles, however, do not tell us which brain structures have been compromised. Fortunately, the MRI studies have also provided valuable clues as to what neuronal structures are abnormal in schizophrenia.

The anterior hippocampus and the surrounding temporal cortex appear to be structures that are smaller in schizophrenics than controls

*References [44] [45] [46] [75] [88] [93] [96] [104] [105] [110] [111] [118] [119] [122] [126] [132] [136] [139] [145] [146] , and [161] .

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as seen on MRI scans. [51] [158] The most replicated postmortem findings of structural abnormalities in schizophrenics involve the hippocampus and surrounding cortex, i.e., parahippocampal gyrus/entorhinal cortex (ERC). * Unfortunately, two of the most interesting results from these studies, a disorientation of the orientation of hippocampal pyramidal neurons [97] and a disorganization of the glomeruli in the second layer of the ERC [12] [83] [84] have not been consistently replicated. [99] The latter may be related to the difficulties in matching sections from schizophrenic and control brains based on structural rather than cytoarchitectonic landmarks. [99] This raises the question as to whether many of the structural postmortem studies have similar methodologic flaws. It does not, however, rule out the findings of studies that have measured the entire volume of the structure. The hippocampus/parahippocampal gyrus/ERC remains as a second major locus for the neuropathology of schizophrenia.

Neurochemical analyses of the hippocampus/ERC have not yielded many replicable findings. Two recent findings from our laboratory may indeed be replicable. The first involves a reduction in the neurotensin binding in layer II of the ERC of schizophrenics relative to controls, which suggests that there may be an alteration in neurotensin receptors. [172] The second finding relates to reduced mRNA for cholecystokinin (CCK), [15] a neuromodulator in both GABA interneurons and glutamate projection neurons. In so far as the decreases are in the fifth and sixth layers of the ERC of schizophrenics, it lends support to the hypothesis that there is a problem with information outflow from the ERC to other cortical regions. The two findings [15] [172] taken together suggest that the ERC of schizophrenics has abnormalities in both superficial (possibly input deficits) and deep (output) layers. Both of these findings have been replicated in our laboratory (unpublished observation).

THE PREFRONTAL CORTEX

The third clue involves the prefrontal cortex (PFC). The frontal lobe has long been suspected as a locus for abstract thinking and mental planning [117] [121] [129] . These cognitive abilities are frequently impaired in patients with damage to the PFC and in patients with schizophrenia. [67] [166] In studies referred to earlier, of identical twins who are discordant for schizophrenia, the one test that correctly identified each schizophrenic patient relative to their cotwins involved completion of neuropsychological tests while blood flow was being measured. [167] When normals are asked to perform the Wisconsin Card Sort test (WCST), they have increased blood flow into the dorsolateral PFC (DLPFC). In the "twin study," the schizophrenic cotwin had less blood flow in the DLPFC while performing the WCST relative to the co-twin in every instance. [167]

*References [4] [8] [9] [12] [13] [20] [30] [31] [34] [38] [39] [40] [49] [55] [72] [83] [84] [87] [89] [90] [95] [97] , and [142] .

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Prior to the twin study an impressive body of literature in neuroimaging [11] [37] [64] [81] [101] [115] and neuroimaging linked to neuropsychology [10] [26] [53] [60] [141] [168] [169] implicated the PFC in schizophrenia. This suggests that the DLPFC is another major locus for the neuropathology of schizophrenia, a notion advanced years earlier by a number of scientists. [77] [98]

The search for the neurobiologic substrate of the prefrontal deficit in patients with schizophrenia has lagged behind the progress in the neuroimaging field, perhaps because of the rudimentary techniques in neuropathology that greatly restricted the ability of initial investigators to find anything but fairly obvious abnormalities. However, morphologic changes in the brains of schizophrenics, which have been reported from static measurements of prefrontal cortex volume derived from MRI and postmortem material, are actually subtle. There have been at least a dozen reports of enlarged ventricles overall and reduced gray matter volumes of the prefrontal cortex of patients with schizophrenia. The changes, specifically in prefrontal area, usually only amounts to about a 10% reduction in cortical thickness at most. [32] [134] [143] [149] [178] More direct measurement of prefrontal cortex in postmortem studies has confirmed the reduction in prefrontal cortical thickness in patients with schizophrenia, [127] [147] although it should be acknowledged that neither is statistically significant.

As discussed in the beginning of this article, one of the difficulties associated with anatomic, neuropathologic studies of the human brain is in determining exactly where to look in the brain for cellular and molecular abnormalities. The hypofrontality abnormalities have been reported in orbital frontal, [36] dorsolateral, [26] [165] and medial frontal cortex. [10] These diverse regions of the prefrontal cortex, because they can be included in a broad definition of prefrontal cortex as those regions lying anterior to the premotor strip, [121] actually contain many different cytoarchitectural areas as defined by neuroanatomists. [33] Neuroanatomic tract tracing studies done in the primate have revealed that each cytoarchitectural region had a different complement of cortical connections. In addition, functional studies have indicated that different cytoarchitectural areas are involved in

mediating different aspects of brain function. [70] It may be that all areas of the prefrontal cortex are equally deficient in the brains of patients with schizophrenia and that the apparent "regionality" found in different studies can vary depending on the brain systems activated or needed for a particular task. If this is the case, it may mean that cellular studies of the prefrontal cortex can proceed encompassing fairly large cortical territories. If only some regions of DLPFC are involved in the pathophysiology of schizophrenia, then the focus of the search for the anatomic abnormality needs to be narrowed to those areas involved.

Because the different subdivisions of the prefrontal area are anatomically and functionally distinct, researchers should be cognizant of the particular subarea under investigation in postmortem studies. The DLPFC receives major projections from higher-order association areas in the inferior parietal and superior temporal region and not from primary

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sensory areas, such that highly processed sensory information enters the DLPFC. [61] [121] On the other hand, the medial prefrontal and the orbital prefrontal cortica are more directly linked to limbic rather than sensory regions. Based on the anatomic connections alone, it is difficult to judge one prefrontal cortical region more worthy of study than another, because both sensory processing and limbic-associated emotional deficits are common features of schizophrenia. Perhaps a rationale for focusing on one prefrontal area over another can be gained from reviewing the functional operations performed by specific regions.

The best guidance in terms of narrowing down the cytoarchitectural regions to focus on neuropathologically has emerged from controlled studies on nonhuman primates. One thesis put forth by Goldman-Rakic suggests that a disorder of a generalized working memory function may be enough to explain a majority of the cognitive problems associated with schizophrenia. [69] [70] She suggests a central problem may be the inability of schizophrenics to form accurate internal representations of the external world to correctly guide future behavior. A problem in this one central cognitive domain, she feels, may explain the inability to plan, the inability to focus on relevant information, the inability to monitor speech during a conversation, and the inability to monitor appropriateness of emotions in a social situation. Primate studies demonstrating that neurons in the DLPFC mediate working memory, and human studies showing DLPFC underactivation during the WCST, a "working memory" test indicate that one logical region on which to focus the search for cellular and molecular abnormalities of the human schizophrenic brain may be the DLPFC. The involvement of other prefrontal areas in schizophrenia certainly can not be ruled out.

Surprisingly little is actually known about the cellular or subcellular abnormalities in the cortex of schizophrenic patients and most of the information available has come from the last decade of work on neurotransmitters and neurotransmitter receptors in human

postmortem material. The cellular or neurochemical studies can be divided into three general groups as follows: (1) those focused on local circuit gamma-aminobutyric acid (GABA) neurons; (2) those focused on glutamate pyramidal projection neurons; and (3) those focused on terminals of brainstem monoamine neurons. In an effort to conceptually review postmortem findings in schizophrenia research, rather than supplying a comprehensive review of results in diverse regions, studies involving the PFC will be the focus of discussion.

GABA INTRANEURONS

First, let us consider the evidence that the local circuit neurons of the cortex may be abnormal in the brains of patients with schizophrenia. The fast-acting inhibitory neurotransmitter used by local circuit neurons is GABA and the critical enzyme regulating its biosynthesis is glutamic acid decarboxylase (GAD). [113] It has been hypothesized that GABA-ergic

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neurotransmission may be altered in the schizophrenic cortex. In support of this idea, a decrease in GAD activity and mRNA [3] [29] [151] , a decrease in GABA uptake binding, [138] [153] and a reduction in GABA release, [151] all of which could reflect reduced GABA synthesis and fewer GABA terminals, have been reported in the cortex of patients with schizophrenia. Also, a potentially compensatory increase in 3 H-muscimol binding to the GABAA receptor especially within superficial layers of the cortex of patients with schizophrenia has been found. [22] [71] This change, however, is not reflected in changes of GABA receptor subunit mRNA levels. [2] The putative decrease of GABAergic tone of the prefrontal cortex has been thought to possibly relate to diminution in the number of interneurons especially in layer II of the PFC. [19] Because a decreased number of GABA neurons is not found in every schizophrenic case [3] a decrease in interneurons may be evident in only a select subpopulation of schizophrenics. Therefore, a reduction in GABA neuron number alone probably does not explain the more generalizable change in GABAergic parameters reported. Thus, one can postulate that if the neurons are situated in the PFC of patients with schizophrenia in relatively normal numbers, they probably are underactive in terms of GABAergic neurotransmission.

The putative decreases in GABAergic neurotransmission may simply parallel a decrease in excitatory neurotransmission in the PFC of patients with schizophrenia. This is consistent with the observation that GABA parameters have been found to downregulate with less afferent activity in the cortex of primates. [23] [24] [74] Also, a second point to consider is that GABA plays a role in inhibiting other GABAergic neurons within the cortex. Therefore, the net effect of the inhibitory neurons which synapse on the pyramidal neurons is unclear. More work characterizing the hypothesized GABAergic abnormality at the regional, cellular, and subcellular levels is necessary to understand the potential significance of this finding to cortical processing and cortical function in the brains of patients with schizophrenia.

GLUTAMATE PYRAMIDAL NEURONS

Next let us consider the evidence that the glutamate neurons of the prefrontal cortex may be abnormal. Glutamate levels are reduced in cerebrospinal fluid of patients with schizophrenia. [92] Glutamate receptor antagonists can cause a psychosis in normal individuals that resembles schizophrenia. [7] [52] [85] The glutamate biosynthetic pathway can involve the conversion of N-acetylaspartylglutamate (NAAG, which antagonizes the action of glutamate) into NAA and glutamate by the NAALADase enzyme. In postmortem studies on prefrontal cortex, both NAALADase activity and glutamate content were significantly reduced in patients with schizophrenia compared with normals, suggesting that there is an overall decrease in glutamate neurotransmission in the prefrontal cortex. [162] In vivo brain measurements of NAA by MRI spectroscopy are reduced within the PFC of patients with schizophrenia [27] [28] also

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suggesting that there may be less production of glutamate in the PFC of patients with schizophrenia. Additionally, a possible compensatory increase in the glutamate receptor complex has been reported in postmortem studies of the PFC of schizophrenics [49] [82] [123] further supporting the notion of an underactive glutamate system in PFC of patients with schizophrenia. Anatomically, the pyramidal neurons of the PFC are usually reported to be found in normal numbers. [22] [147] Because many of these neurons project away from the PFC the putative alterations in glutamate found in the PFC may actually reflect changes in afferents to the PFC. Interestingly, a decrease in mRNA for cholecystokinin, a possible marker of glutamate projection neurons, in the fifth and sixth layers of ERC of schizophrenics relative to controls could relate to a decrease in glutamate efferents to PFC. Lastly, glutamate-related abnormalities have been reported in a number of other brain regions in schizophrenia, especially the temporal lobe. [72] [95] [124] [125]

MONOAMINE INNERVATION OF THE PREFRONTAL CORTEX

It has been shown that the PFC of primates has one of the densest dopaminergic innervations of the entire cortical mantle. [106] [108] [109] Additionally, D2-like dopamine receptor mRNAs and protein have been localized to local circuit neurons in the PFC, [120] suggesting that the GABA-ergic population may be directly and the glutamatergic population may be indirectly responsive to modulation by neuroleptics. Many dopamine afferents to the PFC make synaptic contacts on spines of pyramidal neurons [100] [155] and are thought to primarily inhibit pyramidal neuronal firing. [70] Physiologic studies have shown that dopamine agonists cause increased spontaneous GABA release, [137] possibly leading to a GABA-mediated inhibition of pyramidal neuron excitability. Direct and indirect dopamine modulation of prefrontal cortex afferent activity could be mediated by at least four different receptor subtypes, inhibitory and excitatory D1, D2, D4, and D5 receptors; all of which are present in primate neocortex. [25] [78] [120] [155] There can be interaction between these molecularly distinct dopamine receptors as some of D2 receptor mediated effects

may be dependent on the presence of D1 receptors. [175] The differential anatomic distribution of and the biochemical diversity of dopamine receptor subtypes suggests that the mechanism of dopamine effects on prefrontal cortex are complex. Further complexity is added when the concentration dependent actions of dopamine are considered. Iontophoresis of dopamine antagonists has been shown to enhance pyramidal neuron firing at median doses and to inhibit firing at low or high doses. [170] It has been postulated that hypoactivity of dopamine afferents may interfere with normal pyramidal neuronal activity during a delay period, and may cause working memory deficits. [70] Indeed, chemical lesioning of the dopamine innervation to the DLPFC impairs delayed response task performance of non-human primates. [35] Moreover, lower levels of ventricular dopamine metabolites correlate with reduced cortical

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activity during the WCST. [169] Also, reduction in cortical tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, detected by immunohistochemistry is perhaps the most direct evidence to date of decreased dopamine input to the cortex of schizophrenic patients. [5] [6]

Because of the complex actions of dopamine in the PFC, it is difficult to hypothesize what alterations in dopamine receptors may be expected in the prefrontal cortex of schizophrenic patients. If there proves to be less dopaminergic innervation of the prefrontal cortex, one may speculate that a compensatory upregulation of receptors may exist. However, the D1 receptor density as determined by autoradiography is not altered in the DLPFC of schizophrenic patients. [94] In humans, the effect that chronically altered cortical dopamine levels would have on dopaminergic receptor levels is not clear; nor is the effect that acute and chronic treatment with neuroleptics would have on dopamine receptor levels. Postmortem studies on brains from patients with schizophrenia usually include those on neuroleptics and because receptors are modulated by neuroleptics (as discussed previously), it is difficult to distinguish between primary disease effects and the effects of medication.

Another important neuromodulator of prefrontal cortical activity also derived from the brainstem, is serotonin. Increased attention has been given to this neurotransmitter system in schizophrenia, because of the proposed benefit of atypical neuroleptics, like clozapine, which binds to the 5-HT2 receptors. Serotonin acting in the cortex inhibits the firing of pyramidal neurons. [63] In primate prefrontal cortex, serotonin afferents target GABA interneurons. [154] Also, serotonin receptors (5-HT2) can be localized to GABA interneurons in cortex. [148] Decreases in serotonin reuptake and 5-HT2 receptors sites have been found in the prefrontal cortex of patients with schizophrenia. [102] [118] These findings suggest that there are perhaps both pre-synaptic and post-synaptic abnormalities in the serotonin neurotransmitter system in schizophrenia, although the latter may be an effect of neuroleptic medication.

SYNAPTIC PATHOLOGY

Although there has been no shortage of recent findings in the neuropathology of schizophrenia, hypotheses that can tie findings together have not been abundant. One hypothesis that could bring these diverse findings together is that there are abnormal connections perhaps involving circuits between and among the hippocampus/ERC, DLPFC, and the striatum/nucleus accumbens. Evidence to support this notion would involve studies of the neuropil or more specific measurements of synaptic proteins or their mRNAs. There is increasing evidence to support the hypothesis that there are abnormal connections in the cortex of patients with schizophrenia.

As noted earlier, the gray matter PFC volume is reduced in schizophrenia. [127] More recent studies suggest that there is a concomitant increase in cell packing density in the DLPFC. [48] [147] It has been suggested

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that there may be reduced neuropil in the DLPFC of patients with schizophrenia. [147] Also, an increase in phospholipid break-down products found on brain imaging studies may represent less neuropil. [50] [131] [157] [171] Neuropil, an often ill-defined term referring to the space between Nissl stained neurons, is composed of neuronal processes, axon terminals, dendritic spines, astrocyte processes, astrocyte end-feet, and blood capillaries. Also, synapses are a major component of neuropil and a diminution of the number of synapses has been suggested by reports of fewer dendritic spines on layer III pyramidal neurons, [62] [65] but other neuropil components may be diminished in the DLPFC of patient with schizophrenia as well. Glutamate and dopamine afferents terminate on dendritic spines, whereas GABA terminals are often found on dendritic shafts and cell bodies. The decrease in numbers of spines may represent a decrease in glutamate and dopamine inputs to the cortical pyramidal neuron, and may result in abnormal modulation of the glutamate output neurons of the DLPFC of schizophrenics. Conceptually, the idea of less glutamate afferent input and possibly less overall excitability of the DLPFC in patients with schizophrenia easily meshes with the concept of hypofrontality previously discussed in text. This overly simplistic view may be too naive given the limited amount of cellular resolution and the debate over what a blood flow image is actually measuring on a cellular or subcellular level. Still, it may have some heuristic value.

Another way to investigate the possibility of reduced afferent input into the DLPFC is to measure presynaptic proteins found in afferent terminals in the DLPFC. There has been a recent explosion in knowledge about the molecular machinery involved in the controlled vesicular release of neurotransmitter and vesicular recycling and fifty or more identified proteins are known to be targeted preferentially to presynaptic nerve endings. [160] The only presynaptic protein thus far found to be reduced in the DLPFC of patients with schizophrenia is synaptophysin. [66] [130] Synaptophysin is an integral membrane component of small synaptic vesicles and is present in almost all axons (>90%); therefore, one can not distinguish which afferents might be reduced in the DLPFC of patients with schizophrenia. The reduction of synaptophysin in schizophrenics is found in all layers of the DLPFC and this could implicate more than just one afferent system. [66] Since some

presynaptic nerve terminal proteins are selectively expressed in certain types of neurons and not in others, [112] [152] [160] [163] the measurement of these more selectively distributed synaptic proteins may help to further characterize those terminals which are effected in the DLPFC of patients with schizophrenia. The molecular/chemical definition, along with the neuroanatomical descriptions of the disrupted DLPFC connections, seems to be a very promising area in which to direct future research efforts.

ORIGIN

If there is an abnormal neural circuit in schizophrenia with synaptic pathology involving the hippocampus/ERC, the DLPFC and the

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striatum/nucleus accumbens, then this raises a number of questions including how and why it came about? Genes, [14] viruses, [177] or obstetric complications [116] could interact with a neurodevelopmental program [165] to bring about changes in brain structure or function. The studies reviewed here and elsewhere, [164] support the view that early onset, nonprogressive, structural abnormalities in the temporal lobe and PFC, which are linked via pyramidal glutamate neurons, somehow relate to a peripubertal onset of subcortical dopaminergic abnormalities, psychosis, and cognitive deficits. Although the nature of the early brain lesion in schizophrenia is not known at this time, the neurobiologic substrates of normal peripubertal human brain changes are likely numerous. They probably include changes in dopamine, serotonin, norepinephrine, glutamate, GABA, and acetyl-choline neurotransmitter systems. [16] [34] [43] [72] [102] [113] [114] [139] Additionally, the onset of schizophrenia in late adolescence or young adulthood may be related to the myelination of neocortical regions [17] [21] [176] or the synaptic pruning that both occur at the latter stages of brain development.

Studies on nonhuman primates and normal human neocortex have shown that major synaptic regression occurs in the neocortex around puberty. [79] [135] It may be that synaptic regression underlies the emergence of the adult-level functioning achieved by the DLPFC around puberty. [58] [59] [68] [165] Feinberg was one of the first to suggest that synaptic pruning events associated with normal puberty may fail in patients with schizophrenia [58] [59] [91] and that the schizophrenic brain may actually contain an altered number of connections from what is necessary for optimal functioning. The recent findings of less synaptic proteins and fewer dendritic synaptic profiles suggest that there may actually be an over pruning of synapses in the schizophrenic brain at puberty or perhaps even a normal pruning of an initially reduced neuron number. [107] [164] Owing to the temporal coincidence of synaptic pruning, emergence of adult-level cognitive ability and the onset of schizophrenia, delineating anatomic and molecular changes in growth factors, growth factor receptors, and growth hormone receptors during human brain development and measuring their levels in brains of patients with schizophrenia seem advisable. [164]

CONCLUSION

Regardless, the tools of molecular biology will now permit the measurements of mRNAs of a number of synaptic membrane and brain development proteins. Application of these approaches to the neuropathology of schizophrenia offers the hope and promise of improved understanding of the pathophysiology, cause, and new treatment, if not prevention. Advances will, it is hoped, include new treatment for cognitive deficits that may be the most disabling aspects of the schizophrenic syndrome. This may be accomplished as in PD by appreciating some of the pathophysiology. It is also hoped that these new approaches will go

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beyond this model to undercover the cause or causes of this devastating syndrome.

ACKNOWLEDGMENT

The authors would like to thank Ms Christina Wynn for her help in preparing this manuscript and Dr Susan Bachus for her careful review of this article.

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