The role of microglia in neuropsychiatric disorders and suicide.

This narrative review examines the possible role of microglial cells, first, in neuroinflammation and, second, in schizophrenia, depression, and suicide. Recent research on the interactions between microglia, astrocytes and neurons and their involvement in pathophysiological processes of neuropsychiatric disorders is presented. This review focuses on results from postmortem, positron emission tomography (PET) imaging studies, and animal models of schizophrenia and depression. Third, the effects of antipsychotic and antidepressant drug therapy, and of electroconvulsive therapy on microglial cells are explored and the upcoming development of therapeutic drugs targeting microglia is described. Finally, there is a discussion on the role of microglia in the evolutionary progression of human lineage. This view may contribute to a new understanding of neuropsychiatric disorders.

Reduced ribosomal DNA transcription in the prefrontal cortex of suicide victims: consistence of new molecular RT-qPCR findings with previous morphometric data from AgNOR-stained pyramidal neurons.

Prefrontal cortical regions play a key role in behavioural regulation, which is profoundly disturbed in suicide. The study was carried out on frozen cortical samples from the anterior cingulate cortex (dorsal and ventral parts, ACd and ACv), the orbitofrontal cortex (OFC), and the dorsolateral cortex (DLC) obtained from 20 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 21 non-suicidal controls. The relative level of ribosomal RNA (rRNA) as a marker of the transcriptional activity of ribosomal DNA (rDNA) was evaluated bilaterally in prefrontal regions mentioned above (i.e. in eight regions of interest, ROIs) by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The overall statistical analysis revealed a decrease in rDNA activity in suicide victims versus controls, particularly in male subjects. Further ROI-specific post hoc analyses revealed a significant decrease in this activity in suicides compared to non-suicides in five ROIs. This effect was accentuated in the ACv, where it was observed bilaterally. Our findings suggest that decreased rDNA transcription in the prefrontal cortex plays an important role in suicide pathogenesis and corresponds with our previous morphometric analyses of AgNOR-stained neurons.

Ribosomal DNA transcription in prefrontal pyramidal neurons is decreased in suicide.

Prefrontal cortical regions, which are crucial for the regulation of emotionally influenced behaviour, play most probably a dominant role in the pathogenesis of suicide. The study was carried out on paraffin-embedded brain tissue blocks containing specimens from the anterior cingulate cortex (dorsal and ventral parts), the orbitofrontal cortex, and the dorsolateral cortex obtained from 23 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 25 non-suicidal controls. The transcriptional activity of ribosomal DNA (rDNA) as a surrogate marker of protein biosynthesis was evaluated separately in layers III and V pyramidal neurons in regions of interest (ROIs) mentioned above by the AgNOR silver staining method bilaterally. The overall statistical analysis revealed a decrease of AgNOR area suggestive of attenuated rDNA activity in suicide victims versus controls, particularly in male subjects. Further ROI-specific post-hoc analyses revealed decreases of the median AgNOR area in suicides compared to non-suicides in all 16 ROIs. However, this effect was only significant in the layer V pyramidal neurons of the right ventral anterior cingulate cortex. Our findings suggest that decreased rDNA transcription in prefrontal pyramidal neurons plays possibly an important role in suicide pathogenesis.

Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders.

An involvement of the central serotonergic system has constantly been reported in the pathogenesis of suicide. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour, in which an abnormal microglia reaction seems to play a role. In our present study, the density of microglia immunostained for the HLA-DR antigen was evaluated in the DRN. These analyses were carried out on paraffin-embedded brains from 24 suicidal and 21 non-suicidal patients; among them, 27 depressed (15 major depressive disorder and 12 bipolar disorder) and 18 schizophrenia (9 residual and 9 paranoid) patients and 22 matched controls without mental disorders. Only the non-suicidal depressed subgroup revealed significantly lower microglial reaction, i.e., a decreased density of HLA-DR positive microglia versus both depressed suicide victims and controls. The effect was not related to antidepressant or antipsychotic medication, as the former correlated positively with microglial density in non-suicidal depressed patients, and the latter had no effect. Moreover, the comparison of these results with previously published data from our workgroup in the same cohort (Krzyzanowska et al. in Psychiatry Res 241:43-46, 4) suggested a positive impact of microglia on ribosomal DNA transcription in DRN neurons in the non-suicidal depressed subgroup, but not in depressed suicidal cases. Therefore, the interaction between microglia and neurons in the DRN may be potentially involved in opposite ways regarding suicide facilitation and prevention in the tested subgroups of depressed patients.

Decreased ribosomal DNA transcription in dorsal raphe nucleus neurons is specific for suicide regardless of psychiatric diagnosis.

The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour. We have evaluated the transcriptional activity of ribosomal DNA (rDNA) in DRN neurons by AgNOR silver staining method. The cohort (containing 24 suicidal and 20 non-suicidal patients, and 28 controls) was previously analysed regarding diagnosis-related differences between schizophrenia and affective disorders. Significant decreases in both AgNOR and nuclear areas suggestive of attenuated rDNA activity were currently found in suicidal versus non-suicidal patients. This effect, which was more accentuated in affective disorders patients, was not explained by antidepressant and antipsychotic medication.

GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study.

BACKGROUND: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and residual schizophrenia. METHODS: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem schizophrenia patient samples (10 paranoid and 6 residual schizophrenia cases) were compared with those from 16 matched controls. RESULTS: Overall, schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus residual schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). CONCLUSION: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system.

Volumetric analysis of the diagonal band of Broca in patients with schizophrenia and affective disorders: A post-mortem study.

The human diagonal band of Broca is connected to other parts of the limbic system, such as the hippocampus, that are involved in the pathology of schizophrenia. This study aimed to characterize the volume and anterior-to-posterior distance of the human diagonal band of Broca (vertical limb) from post-mortem brains obtained from three groups: healthy control subjects (N = 17), patients with schizophrenia (N = 26), and patients with affective disorders (N = 12). There were no significant differences in the volume or anterior-to-posterior distance in the patients with schizophrenia or affective disorders compared with the healthy control subjects. To date, this is the first post-mortem investigation measuring the volume and the anterior-to-posterior distance of the diagonal band of Broca (vertical limb) in patients with schizophrenia or affective disorders compared with healthy control subjects.

Decreased ribosomal DNA transcription in dorsal raphe nucleus neurons differentiates between suicidal and non-suicidal death.

An involvement of the central serotonergic system has been implicated in the pathogenesis of suicide. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour. The study was carried out on paraffin-embedded brainstem blocks containing the DRN obtained from 27 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 30 non-suicidal controls. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons as a surrogate marker of protein biosynthesis was evaluated by the AgNOR silver staining method. Significant decreases in AgNOR parameters suggestive of attenuated rDNA activity were found in the cumulative analysis of all DRN subnuclei in suicide victims versus controls (U test P values < 0.00001). Our findings suggest that the decreased activity of rDNA transcription in DRN neurons plays an important role in suicide pathogenesis. The method accuracy represented by the area under receiver operating characteristic curve (>80 %) suggests a diagnostic value of the observed effect. However, the possible application of the method in forensic differentiation diagnostics between suicidal and non-suicidal death needs further research.

Bilaterally reduced claustral volumes in schizophrenia and major depressive disorder: a morphometric postmortem study.

Multiple brain structural abnormalities have been reported in schizophrenia and major depressive disorder. A majority of disease-affected brain regions act as relay nodes within neural networks, which are known to be impaired in neuropsychiatric diseases. One of these regions is the claustrum, which has the highest connectivity in the human brain by regional volume. Its possible involvement in disturbed connectivity is yet incompletely explored, however. The present study aimed at searching for possible structural deviations of the claustrum in neuropsychiatric disorders. We found bilaterally reduced claustral volumes both in schizophrenia and in major depressive disorder. These structural impairments may have different, disease-related consequences: In patients with schizophrenia, they may contribute to sensory processing impairments, and in patients with major depressive disorder to disturbances in salience.

Calretinin and parvalbumin in schizophrenia and affective disorders: a mini-review, a perspective on the evolutionary role of calretinin in schizophrenia, and a preliminary post-mortem study of calretinin in the septal nuclei.

OBJECTIVE: The septal nuclei are important limbic regions that are involved in emotional behavior and connect to various brain regions such as the habenular complex. Both the septal nuclei and the habenular complex are involved in the pathology of schizophrenia and affective disorders. METHODS: We characterized the number and density of calretinin-immunoreactive neurons in the lateral, medial, and dorsal subregions of the septal nuclei in three groups of subjects: healthy control subjects (N = 6), patients with schizophrenia (N = 10), and patients with affective disorders (N = 6). RESULTS: Our mini-review of the combined role of calretinin and parvalbumin in schizophrenia and affective disorders summarizes 23 studies. We did not observe significant differences in the numbers of calretinin-immunoreactive neurons or neuronal densities in the lateral, medial, and dorsal septal nuclei of patients with schizophrenia or patients with affective disorders compared to healthy control subjects. CONCLUSIONS: Most post-mortem investigations of patients with schizophrenia have indicated significant abnormalities of parvalbumin-immunoreactive neurons in various brain regions including the hippocampus, the anterior cingulate cortex, and the prefrontal cortex in schizophrenia. This study also provides an explanation from an evolutionary perspective for why calretinin is affected in schizophrenia.

Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in residual schizophrenia compared to depressed patients with affective disorders.

The central serotonergic system is implicated differentially in the pathogenesis of depression and schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 schizophrenia (9 residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in residual (but not paranoid) schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in residual schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.

Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia.

The central serotonergic system is implicated in the pathogenesis of schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 residual) schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in schizophrenia patients in the cumulative analysis of all DRN subnuclei (t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for residual schizophrenia versus paranoid schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in schizophrenia, particularly in residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.

The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue.

Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

Volumetric analysis of the hypothalamus, amygdala and hippocampus in non-suicidal and suicidal mood disorder patients--a post-mortem study.

In recent years, the hypothalamus, amygdala and hippocampus have attracted increased interest with regard to the effects of stress on neurobiological systems in individuals with depression and suicidal behaviour. A large body of evidence indicates that these subcortical regions are involved in the pathogenetic mechanisms of mood disorders and suicide. The current neuroimaging techniques inadequately resolve the structural components of small and complex brain structures. In previous studies, our group was able to demonstrate a structural and neuronal pathology in mood disorders. However, the impact of suicide remains unclear. In the current study we used volumetric measurements of serial postmortem sections with combined Nissl-myelin staining to investigate the hypothalamus, amygdala and hippocampus in suicide victims with mood disorders (n = 11), non-suicidal mood disorder patients (n = 9) and control subjects (n = 23). Comparisons between the groups by using an ANCOVA showed a significant overall difference for the hypothalamus (p = 0.001) with reduced volumes in non-suicidal patients compared to suicide victims (p = 0.018) and controls (p = 0.006). To our surprise, the volumes between the suicide victims and controls did not differ significantly. For the amygdala and hippocampus no volume changes between the groups could be detected (all p values were n. s.). In conclusion our data suggest a structural hypothalamic pathology in non-suicidal mood disorder patients. The detected differences between suicidal and non-suicidal patients suggest that suicidal performances might be related to the degree of structural deficits.

Ribosomal DNA transcription in the anterior cingulate cortex is decreased in unipolar but not bipolar I depression.

The anterior cingulate cortex (AC) is consistently implicated in the pathophysiology of depression. However, it is not clear whether unipolar and bipolar depression display distinct neuropathological features. Therefore, the objective of this post-mortem study was to re-evaluate this important issue. Brains from 9 patients with major depressive disorder (MDD) and 11 patients with bipolar disorder (BD) subtype I depression as well as 24 matched controls were analysed. The argyrophilic nucleolar organiser region (AgNOR) silver-staining method was applied on paraffin-embedded brain sections in order to assess the transcriptional activity of ribosomal DNA (rDNA) in layer III and V pyramidal neurons of the dorsal and ventral AC in both hemispheres. An AgNOR area decrease suggestive of a diminished transcriptional activity of rDNA was found in the MDD group both versus controls and versus the BD group. The effect was specific for the right hemisphere and dorsal AC and was restricted to layer V pyramidal neurons. The results suggest that only patients with MDD display region-specific chronic hypoactivity of these output neurons, which are critical for mood regulation. Furthermore, in our cohort, unipolar and bipolar I depression could be differentiated relative to the presumed AC hypoactivity and psychotropic medication did not counteract the observed effect.

Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations?

Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.

Immunohistochemical evidence for impaired nitric oxide signaling of the locus coeruleus in bipolar disorder.

Nitric oxide (NO) is an important messenger in brain signaling and influences the balance of monoaminergic and glutamatergic neurotransmission. Alterations of NO signaling are thought to play a crucial role in the pathophysiology of mood disorders. The locus coeruleus (LC) comprises the largest group of norepinephrine containing neurons in the mammalian brain. These norepinephrinergic LC neurons are able to generate NO. Immunohistochemical staining of neuronal nitric oxide synthase (nNOS)-immunoreactive (ir) neurons was performed in the LC of the brains of 10 patients with bipolar I disorder (BD), 8 patients with major depressive disorder (MDD) and 16 control cases (C). Analysis of variance (ANOVA) revealed significant differences between the groups, and post hoc tests indicated a lower nNOS-ir neuron number in bipolar patients than in controls (left -34%, right -17%). The total number of Nissl-stained LC neurons showed no changes between major depressive disorder patients, bipolar patients and controls. In the mood disorder patients, illness duration correlated negatively with nNOS-ir neuronal number (r=-0.74, p=0.002). A reduced relative amount of NO in the LC of bipolar patients is likely a result of a compensation for increased glutamatergic activity. The current data on nNOS suggest a dysregulation of the nitrergic system in bipolar disorder. Future studies may clarify the potential role of glial cells in the context of the described nNOS deficit.

Differences between unipolar and bipolar I depression in the quantitative analysis of glutamic acid decarboxylase-immunoreactive neuropil.

Alterations in GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme in GABA synthesis. This study aimed to differentiate between unipolar and bipolar I depression using quantitative evaluation of GAD-immunoreactive (GAD-ir) neuropil in several brain regions known to be involved in the pathophysiology of mood disorders. Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLPFC), the entorhinal cortex, the hippocampal formation and the medial dorsal and lateral dorsal (LD) thalamic nuclei, with a quantitative densitometric analysis of GAD-ir neuropil. The study was performed on paraffin-embedded brains from 9 unipolar and 12 bipolar I depressed patients (8 and 6 suicidal patients, respectively) and 18 matched controls. In unipolar patients, compared with controls, only the increased relative density of GAD-ir neuropil in the right LD was different from the previous results in depressed suicides from the same cohort (Gos et al. in J Affect Disord 113:45-55, 2009). On the other hand, the left DLPFC was the only area where a significant decrease was observed, specific for bipolar I depression. Significant differences between both diagnostic groups were found in these regions. By revealing abnormalities in the relative density of GAD-ir neuropil in brain structures, our study suggests a diathesis of the GABAergic system in mood disorders, which may differentiate the pathophysiology of unipolar from that of bipolar I depression.

A postmortem assessment of mammillary body volume, neuronal number and densities, and fornix volume in subjects with mood disorders.

Mammillary bodies are relay nuclei within limbic and extralimbic connections. Whereas other subcortical brain structures have been found to be altered in depression, no current information exists regarding the pathomorphology of mammillary bodies in affective disorders. We studied the postmortem brains of 19 human subjects with mood disorders (9 with major depressive disorder and 10 with bipolar I disorder) and 20 control individuals and assessed the mammillary body and fornix volumes, number of neurons and neuronal densities. We found that male control subjects have significantly larger mammillary bodies compared with females. In addition, control subjects of both sexes with the diagnosis/cause of death of "heart failure/insufficiency" had significantly smaller mammillary body volumes compared with non-psychiatric patients who died from other causes. When estimating the mammillary bodies volumes of patients with depression compared with control subjects, a significant reduction of the left mammillary body volume was found in patients with bipolar disorder, but not in patients with major depression. However, significant depression-associated mammillary body volume reductions were found between the control subjects who did not die of heart failure and patients with major depression and bipolar disorder. Moreover, the MB volumes of control subjects who died of heart failure were in the range exhibited by subjects with depression. There was no significant influence of suicidal behavior on mammillary volumes observed. Moreover, no significant group differences in the total neuronal number or neuronal density were found between the controls, subjects with major depression and subjects with bipolar disorder. Furthermore, the fornix volumes were significantly reduced only in the control subjects with heart failure. Taken together, these results show that the mammillary bodies are compromised in depression.

Reduced density of hypothalamic VGF-immunoreactive neurons in schizophrenia: a potential link to impaired growth factor signaling and energy homeostasis.

Protein expression of VGF (nonacronymic) is induced by nerve/brain-derived growth factor, neurotrophin 3, and insulin. VGF is synthesized by neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. After enzymatic processing, smaller VGF-derived peptides are secreted into the cerebrospinal fluid (CSF) or blood. These peptides play important roles by improving synaptic plasticity, neurogenesis, and energy homeostasis, which are impaired in schizophrenia. Based on previous observations of neuroendocrine and hypothalamic deficits in schizophrenia and to determine whether increased levels of the VGF fragment 23-62 in CSF, which have been described in a recent study, were related to changes in hypothalamic VGF expression, an immunohistochemical study was performed in 20 patients with schizophrenia and 19 matched control subjects. N- (D-20) and C-terminal (R-15) VGF antibodies yielded similar results and immunolabeled a vast majority of PVN and SON neurons. Additionally, D20-VGF immunohistochemistry revealed immunostained fibers in the pituitary stalk and neurohypophysis that ended at vessel walls, suggesting axonal transport and VGF secretion. The cell density of D20-VGF-immunoreactive neurons was reduced in the left PVN (P = 0.002) and SON (P = 0.008) of patients with schizophrenia. This study provides the first evidence for diminished hypothalamic VGF levels in schizophrenia, which might suggest increased protein secretion. Our finding was particularly significant in subjects without metabolic syndrome (patients with a body mass index ≤28.7 kg/m(2)). In conclusion, apart from beneficial effects on synaptic plasticity and neurogenesis, VGF may be linked to schizophrenia-related alterations in energy homeostasis.