Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis.

Immunological and inflammatory reactions have been suggested to have a role in the development of schizophrenia, a hypothesis that has recently been supported by genetic data. The aim of our study was to perform an unbiased search for autoantibodies in patients with a first psychotic episode, and to explore the association between any seroreactivity and the development of a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder characterized by chronic or relapsing psychotic symptoms. We collected plasma samples from 53 patients when they were treated for their first-episode psychosis, and 41 non-psychotic controls, after which the patients were followed for a mean duration of 7 years. Thirty patients were diagnosed with schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder or a long-term unspecified nonorganic psychosis during follow-up, whereas 23 patients achieved complete remission. At the end of follow-up, plasma samples were analyzed for IgG reactivity to 2304 fragments of human proteins using a multiplexed affinity proteomic technique. Eight patient samples showed autoreactivity to the N-terminal fragment of the PAGE (P antigen) protein family (PAGE2B/PAGE2/PAGE5), whereas no such autoreactivity was seen among the controls. PAGE autoreactivity was associated with a significantly increased risk of being diagnosed with schizophrenia during follow-up (odds ratio 6.7, relative risk 4.6). An immunohistochemistry analysis using antisera raised against the N-terminal fragment stained an unknown extracellular target in human cortical brain tissue. Our findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis.

Psychiatric symptoms and disorders in HIV infected mine workers in South Africa. A retrospective descriptive study of acute first admissions.

OBJECTIVE: The social and living conditions of mine workers in South Africa contribute to a rapid transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections. HIV-associated dementia is a serious condition during HIV disease. Several other psychiatric symptoms and disorders, such as psychosis, secondary mania and depression, have also been associated with clinical HIV infection. We describe the onset of psychiatric symptoms and signs in a group of untreated, HIV infected male mine workers first admitted for psychiatric treatment at the Rand Mutual Hospital in Johannesburg. METHOD: Between 1987 and 1997, 38 consecutive cases were admitted, and their files were retrieved for study in 2006. The subjects were 38 black male mine workers admitted acutely for psychiatric care due to psychiatric symptoms, and subsequently diagnosed with HIV infection. The presenting psychiatric symptoms on admission and diagnoses at discharge were compiled for all patients, not to infer causality but to establish the range of symptoms that the clinician has to deal with. RESULTS: The 38 patients presented with a wide range of psychiatric symptoms. The dominating symptoms were those of cognitive deficits, and different psychotic manifestations. 12 of the patients, almost one third of the individuals, were diagnosed with dementia. The patients with dementia exhibited cognitive deficits, and in addition often abnormal behaviour and psychotic symptoms, and several also had symptoms of secondary mania. 5 of the patients presented with delirium. Psychosis, without concurrent dementia, was diagnosed in 5 patients. Bipolar disorder with mania, without concurrent dementia, and major depression was present in 2 patients, respectively. Screening for substance abuse showed that 9 of the patients had ongoing cannabis abuse and 10 had alcohol abuse. Cannabis-induced psychotic disorder was present in 5 patients. CONCLUSION: The findings confirm that patients with a new diagnosis of HIV may present with disorders of thought and/or cognition as well as gross behavioural disturbance, and that psychotic symptoms and secondary mania could be manifestations of the clinical onset of HIV/acquired immune deficiency syndrome (AIDS) infection.

HIV infection and psychiatric illness.

OBJECTIVE: To review the clinical features and current knowledge on the treatment of psychiatric symptoms and disorders in patients with human immunodeficiency virus (HIV) infection. METHOD: We searched the PubMed database combining HIV/AIDS with different keywords for psychiatric diagnoses and symptoms (e.g. depression, mania, anxiety, psychosis, dementia, substance abuse) and for psychopharmacological treatment. The years covered by these searches included 1980 to 2008. RESULTS: Patients with HIV infection are at an increased risk of psychiatric illness. Major depressive disorder and subsyndromal depressive symptoms, as well as anxiety disorder and substance abuse are more prevalent among HIV infected individuals than among the general population. HIV-associated neurocognitive disorders (HAND) are common among HIV patients, and HIV-associated dementia (HAD) is a serious condition during the acquired immune deficiency syndrome (AIDS) stage of HIV disease. Secondary mania and psychosis might be the first clinical symptom of HIV dementia. The introduction of highly active anti-retroviral therapy (HAART) has resulted in significant decreases in morbidity and mortality for HIV infected patients. HAART has also decreased the incidence of HAD, but does not give complete protection from this condition. The utility of psychotropic medications in HIV patients has not been studied sufficiently as a basis for guidelines, and more controlled trials are needed. CONCLUSION: Psychiatric illness is common in HIV infected individuals, and underlines the importance for screening not only for cognitive impairment but also for co morbid mental disease in HIV-positive patients. Further studies of the neuropsychiatric complications during HIV disease and the use of psychotropics under these circumstances are clearly needed. A better understanding of the pathogenesis of HAD is essential to identify additional therapeutic strategies for prevention and treatment of this neurodegenerative disease. Studies are also needed for optimizing effective utilization of antiretrovirals into the CNS. Mania and psychosis secondary to HAD may be used as an indicator to initiate HAART, irrespective of CD4 count. Further research on the utility of HAART in the treatment of such acute neuropsychiatric symptoms associated with HIV infection should be initiated.

Changes in calcium currents and GABAergic spontaneous activity in cultured rat hippocampal neurons after a neurotropic influenza A virus infection.

In order to study mechanisms by which a neurotropic strain of influenza A virus (A/WSN/33) may affect neuronal function or cause nerve cell death, hippocampal cultures from embryonic rats were infected with this virus. Approximately 70% of the neurons in the infected cultures became immunopositive for viral antigens and showed reduced voltage-dependent Ca(2+) currents in whole-cell patch clamp recordings, but no changes in other membrane properties or in cytosolic Ca(2+) concentration were seen. These immunopositive neurons underwent apoptosis 3-4 days after infection. Ca(2+) channel inhibitors had no significant effect on neuronal survival. The immunonegative population of neurons survived, but displayed increased frequency of miniature inhibitory postsynaptic currents of gamma-amino-butyric acid origin compared with controls. The frequency of alpha-amino-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptor-mediated miniature excitatory postsynaptic currents was not altered. Viral nucleoproteins, overexpressed using the Semliki Forest virus system, were localized to the dendritic spines as shown by double immunolabeling with actinin, but did not by themselves cause neuronal death or changes in synaptic transmission as measured by AMPA-mediated excitatory postsynaptic currents. Our results show that an influenza A virus infection can cause selective neurophysiological changes in hippocampal neurons and that these can persist even after the viral antigens have been cleared.

Interferon-gamma-induced changes in synaptic activity and AMPA receptor clustering in hippocampal cultures.

Extended release of interferon-gamma (IFN-gamma) in the nervous system during immunological and infectious conditions may trigger demyelinating disorders and cause disturbances in brain function. The aim of this study was to examine the effects of IFN-gamma on neuronal function in rat hippocampal cell cultures by using whole cell patch clamp analysis together with quantitative immunocytochemistry. Acute application of IFN-gamma to differentiated neurons in culture caused no immediate neurophysiological responses, but recordings after 48 h of incubation displayed an increase in frequency of AMPA receptor (AMPAR)-mediated spontaneous excitatory postsynaptic currents (EPSCs). Quantitative immunocytochemistry for the AMPAR subunit GluR1 showed no alteration in receptor clustering at this time point. However, prolonged treatment with IFN-gamma for 2 weeks resulted in a significant reduction in AMPAR clustering on dendrites but no marked differences in EPSC frequency between treated neurons and controls could be observed. On the other hand, treatment of hippocampal neurons for 4 weeks, instituted at an immature stage (1 day in culture), caused a significant reduction in spontaneous EPSC frequency. These neurons developed with no overt alterations in dendritic arborization or in the appearance of dendritic spines as visualized by alpha-actinin immunocytochemistry. Nonetheless, there was a marked reduction in AMPAR clustering on dendrites. These observations show that a key immunomodulatory molecule, IFN-gamma, can cause long-term modifications of synaptic activity and perturb glutamate receptor clustering.

Perturbation of the synaptic release machinery in hippocampal neurons by overexpression of SNAP-25 with the Semliki Forest virus vector.

We have examined whether the Semliki Forest virus (SFV) expression vector can be used to manipulate the exocytotic machinery in cultured hippocampal neurons. Autaptic responses were recorded in individually identified neurons which overexpressed either a non-synaptic protein, the transferrin receptor, or the synaptic SNARE protein SNAP-25 (synaptosomal-associated protein of 25 kDA). In neurons overexpressing the transferrin receptor, autaptic responses occurred in a similar proportion and had similar amplitudes (12-18 h postinfection) as in uninfected control neurons. With increasing time after the infection, an increasing proportion of the transferrin receptor-overexpressing neurons showed changes in the shape of the cell body, but the autaptic responses appeared normal as long as recordings could be performed (up to 30 h postinfection). In contrast, in SNAP-25-overexpressing neurons, the proportion of responding cells was reduced 12-18 h after the infection, and the amplitude of the autaptic current in responding neurons was also reduced. The sensitivity to exogenously applied glutamate was, however, unchanged. Biochemical analysis showed that 50% of the overexpressed SNAP-25 was palmitoylated. The levels of two other SNAREs, syntaxin and synaptobrevin (also called vesicle-associated membrane protein), were not affected. Our results indicate that the SFV vector can provide an effective tool to study the function of proteins participating in neurotransmitter release.

Distinct effects of clostridial toxins on activity-dependent modulation of autaptic responses in cultured hippocampal neurons.

Clostridial neurotoxins proteolyse specific proteins implicated in synaptic vesicle exocytosis, but their actions on the release machinery in functional synapses is not well understood. Here we examine the effects of botulinum toxin A (BoNT/A) and tetanus toxin (TeTx) on autaptic transmission in cultured rat hippocampal neurons using whole-cell voltage clamp recordings. The proportion of cells responding to stimulation with an excitatory postsynaptic current (EPSC) and the magnitude of the remaining responses decreased gradually with increasing concentration of either toxin. However, the activity-dependent modulation (5 Hz repetitive stimulation) of EPSCs remaining after toxin inhibition differed markedly between the two toxins. The TeTx inhibition was associated with a persistent activity-dependent depression similar to that in control cells. In contrast, the BoNT/A inhibition was accompanied by a reversal of the modulation into facilitation, resembling that induced by lowering of the calcium concentration. These results demonstrate a difference between BoNT/A and TeTx in their mode of inhibition of synaptic vesicle exocytosis, which suggests that they exert their preferential actions at distinct steps of the release process.

Reduction of voltage-dependent calcium currents in mumps virus-infected cultures of rat hippocampal neurons.

The effects of a mumps virus infection on functional properties of embryonic hippocampal neurons in culture were analysed with special emphasis on voltage-dependent Ca2+ channels. Cultures with higher or lower density of glial cells (not treated or treated with mitotic inhibitor, respectively) were infected with the relatively non-cytolytic RW strain of mumps virus and currents were recorded from neurons using whole cell voltage clamp. More than 65% of neurons and glial cells contained viral antigens 1-2 days post infection (p.i.). Glial cells remained infected 6-7 days p.i., while the ratio of infected versus uninfected neurons, especially in cultures with higher glial cell density, was reduced. In both infected and uninfected cultures the somal voltage-dependent Ca2+ currents were stronger in cultures with a higher glial cell density, which indicates that these currents are influenced by glial cells. Introduction of the virus into cultures caused a selective decrease in inward Ca2+ currents, which was most marked at days 6-7 p.i., and which included both infected and unifected neurons. Spontaneous synaptic currents and other ion channel conductances appeared normal in the infected cultures. Dantrolene, which inhibits release of Ca2+ from intracellular stores, decreased the neurons that died during the infection. Taken together the results show that a mumps viral infection can selectively alter the number of function of somal voltage dependent Ca2+ channels in immature hippocampal neurons and that this may reflect a disturbed glia-nerve cell interaction.