| 1 | Psychiatry Investig 2009 Dec 6: 294-8 |
|---|---|
| PMID | 20140128 |
| Title | The pNNx Heart Rate Variability Statistics: An Application to Neuroautonomic Dysfunction of Clozapine-Treated Subjects. |
| Abstract | The percentage of successive normal cardiac interbeat intervals greater than 50 msec (PNN50) is a widely used heart rate variability measure, which is useful in identifying the neuroautonomic dysfunction of psychiatric disorders. However, PNN50 is only one member of a larger family of PNNx statistics, where x is greater than 0 msec. The potential application of the general PNNx statistics has not yet been explored in the psychiatric field. The authors examined the PNNx statistics in clozapine-treated subjects and normal controls to evaluate the usefulness of the general PNNx statistics. Sixty-one schizophrenic patients treated with clozapine and fifty-nine normal controls were evaluated. Probability values for the differences between the groups at each PNN value (range: PNN1-PNN100) were calculated using data obtained from a 30-minute electrocardiogram. The conventional PNN50 and PNNx values with x<50 msec were all significantly lower in the patient group (p<0.05). The distinction between the two groups was more prominent at PNN values less than 50 msec than that observed at PNN50. The maximum separation between groups occurred at PNN5 (68.2+/-19.1 vs. 22.5+/-20.5, p<10(-22)). The PNNx with x<50 msec provided more robust discrimination between the groups than the conventional PNN50, suggesting the importance of analyzing very small variations of interbeat interval in discriminating normal and pathological heart rate patterns. The results also suggest that the general PNNx statistics may be applied and useful in evaluating the neuroautonomic dysfunction in patients treated with clozapine, complementing the traditionally computed PNN50 value. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Psychiatry Investig 2009 Dec 6: 294-8 |
| PMID | 20140128 |
| Title | The pNNx Heart Rate Variability Statistics: An Application to Neuroautonomic Dysfunction of Clozapine-Treated Subjects. |
| Abstract | The percentage of successive normal cardiac interbeat intervals greater than 50 msec (PNN50) is a widely used heart rate variability measure, which is useful in identifying the neuroautonomic dysfunction of psychiatric disorders. However, PNN50 is only one member of a larger family of PNNx statistics, where x is greater than 0 msec. The potential application of the general PNNx statistics has not yet been explored in the psychiatric field. The authors examined the PNNx statistics in clozapine-treated subjects and normal controls to evaluate the usefulness of the general PNNx statistics. Sixty-one schizophrenic patients treated with clozapine and fifty-nine normal controls were evaluated. Probability values for the differences between the groups at each PNN value (range: PNN1-PNN100) were calculated using data obtained from a 30-minute electrocardiogram. The conventional PNN50 and PNNx values with x<50 msec were all significantly lower in the patient group (p<0.05). The distinction between the two groups was more prominent at PNN values less than 50 msec than that observed at PNN50. The maximum separation between groups occurred at PNN5 (68.2+/-19.1 vs. 22.5+/-20.5, p<10(-22)). The PNNx with x<50 msec provided more robust discrimination between the groups than the conventional PNN50, suggesting the importance of analyzing very small variations of interbeat interval in discriminating normal and pathological heart rate patterns. The results also suggest that the general PNNx statistics may be applied and useful in evaluating the neuroautonomic dysfunction in patients treated with clozapine, complementing the traditionally computed PNN50 value. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Biol. Psychiatry 2013 Sep 74: 427-35 |
| PMID | 23790226 |
| Title | Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. |
| Abstract | Perineuronal nets (PNNs) are extracellular matrix structures that enwrap many neurons in the brain. They regulate the postnatal experience-dependent maturation of brain circuits and maintain their functional integrity in the mature brain by stabilizing their synaptic architecture. Eighty-six postmortem human brains were included in this study. We used Wisteria Floribunda agglutinin histochemistry to visualize PNNs to investigate whether the densities of PNNs in the prefrontal cortex (PFC) and primary visual cortex were altered in subjects with schizophrenia or bipolar disorder. In addition, we quantified the normal postnatal development of PNNs in the human PFC. The densities of PNNs were decreased by 70%-76% in layers 3 and 5 of the PFC in schizophrenia, compared with the normal control subjects, but not in bipolar disorder. This finding was replicated in a separate group of schizophrenia and normal control subjects. In addition, PNN densities in the primary visual cortex were unaltered in either condition. Finally, the number of PNNs in the PFC increased during postnatal development through the peripubertal period until late adolescence and early adulthood. These findings suggest that PNN deficit contributes to PFC dysfunction in schizophrenia. That the timing of PNN development overlaps with the period when schizophrenia symptomatology gradually emerges raises the possibility that aberrant PNN formation might contribute to the onset of illness. Thus, characterization of the molecular mechanisms underlying PNN deficit might have important implications for the conceptualization of novel strategies for the diagnosis, treatment, early intervention, and prevention of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Neurosci Biobehav Rev 2014 Sep 45: 85-99 |
| PMID | 24709070 |
| Title | Perineuronal nets and schizophrenia: the importance of neuronal coatings. |
| Abstract | schizophrenia is a complex brain disorder associated with deficits in synaptic connectivity. The insidious onset of this illness during late adolescence and early adulthood has been reported to be dependent on several key processes of brain development including synaptic refinement, myelination and the physiological maturation of inhibitory neural networks. Interestingly, these events coincide with the appearance of perineuronal nets (PNNs), reticular structures composed of components of the extracellular matrix that coat a variety of cells in the mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been associated with schizophrenia. Here, we review the emerging evidence linking PNNs to schizophrenia. Future studies aimed at further elucidating the functions of PNNs will provide new insights into the pathophysiology of schizophrenia leading to the identification of novel therapeutic targets with the potential to restore normal synaptic integrity in the brain of patients afflicted by this illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Transl Psychiatry 2015 -1 5: e496 |
| PMID | 25603412 |
| Title | Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala. |
| Abstract | Perineuronal nets (PNNs) are specialized extracellular matrix aggregates surrounding distinct neuronal populations and regulating synaptic functions and plasticity. Previous findings showed robust PNN decreases in amygdala, entorhinal cortex and prefrontal cortex of subjects with schizophrenia (SZ), but not bipolar disorder (BD). These studies were carried out using a chondroitin sulfate proteoglycan (CSPG) lectin marker. Here, we tested the hypothesis that the CSPG aggrecan, and 6-sulfated chondroitin sulfate (CS-6) chains highly represented in aggrecan, may contribute to these abnormalities. Antibodies against aggrecan and CS-6 (3B3 and CS56) were used in the amygdala of healthy control, SZ and BD subjects. In controls, aggrecan immunoreactivity (IR) was observed in PNNs and glial cells. Antibody 3B3, but not CS56, also labeled PNNs in the amygdala. In addition, dense clusters of CS56 and 3B3 IR encompassed CS56- and 3B3-IR glia, respectively. In SZ, numbers of aggrecan- and 3B3-IR PNNs were decreased, together with marked reductions of aggrecan-IR glial cells and CS-6 (3B3 and CS56)-IR 'clusters'. In BD, numbers of 3B3-IR PNNs and CS56-IR clusters were reduced. Our findings show disruption of multiple PNN populations in the amygdala of SZ and, more modestly, BD. Decreases of aggrecan-IR glia and CS-6-IR glial 'clusters', in sharp contrast to increases of CSPG/lectin-positive glia previously observed, indicate that CSPG abnormalities may affect distinct glial cell populations and suggest a potential mechanism for PNN decreases. Together, these abnormalities may contribute to a destabilization of synaptic connectivity and regulation of neuronal functions in the amygdala of subjects with major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Schizophr Bull 2015 Jul 41: 835-46 |
| PMID | 26032508 |
| Title | Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia. |
| Abstract | schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Schizophr. Res. 2015 Sep 167: 18-27 |
| PMID | 25601362 |
| Title | Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia. |
| Abstract | Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Neural Plast. 2016 -1 2016: 9847696 |
| PMID | 26839720 |
| Title | In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders. |
| Abstract | Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the "quadripartite" synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Biol. Psychiatry 2016 Mar -1: -1 |
| PMID | 27113498 |
| Title | Weaving a Net of Neurobiological Mechanisms in Schizophrenia and Unraveling the Underlying Pathophysiology. |
| Abstract | Perineuronal nets (PNNs) are enigmatic structures composed of extracellular matrix molecules that encapsulate the soma, dendrites, and axon segments of neurons in a lattice-like fashion. Although most PNNs condense around parvalbumin-expressing gamma-aminobutyric acidergic interneurons, some glutamatergic pyramidal cells in the brain are also surrounded by PNNs. Experimental findings suggest pivotal roles of PNNs in the regulation of synaptic formation and function. Also, an increasing body of evidence links PNN abnormalities to schizophrenia. The number of PNNs progressively increases during postnatal development until plateauing around the period of late adolescence and early adulthood, which temporally coincides with the age of onset of schizophrenia. Given the established role of PNNs in modulating developmental plasticity, the PNN represents a possible candidate for altering the onset and progression of schizophrenia. Similarly, the reported function of PNNs in regulating the trafficking of glutamate receptors places them in a critical position to modulate synaptic pathology, considered a cardinal feature of schizophrenia. We discuss the physiologic role of PNNs in neural function, synaptic assembly, and plasticity as well as how they interface with circuit/system mechanisms of cognition. An integrated understanding of these neurobiological processes should provide a better basis to elucidate how PNN abnormalities influence brain function and contribute to the pathogenesis of neurodevelopmental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Neuropsychopharmacology 2016 Feb -1: -1 |
| PMID | 26868058 |
| Title | Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia. |
| Abstract | Alterations in cortical parvalbumin (PV)-containing neurons, including a reduced density of detectable neurons and lower PV levels, have frequently been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects. Most PV neurons are surrounded by perineuronal nets (PNNs) and the density of PNNs, as detected by Wisteria floribunda agglutinin (WFA) labeling, has been reported to be lower in schizophrenia. However, the nature of these PNN alterations, and their relationship to disease-related changes in PV neurons, has not been assessed. Using confocal microscopy, we quantified the densities and fluorescence intensities of PV neurons and PNNs labeled with WFA or immunoreactive for the major PNN protein, aggrecan, in the DLPFC from schizophrenia and matched comparison subjects. In schizophrenia, the densities of PV cells and of PNNs were not altered; however, the fluorescence intensities of PV immunoreactivity in cell bodies and of WFA labeling and aggrecan immunoreactivity in individual PNNs around PV cells were lower. These findings indicate that the normal complements of PV cells and PNNs are preserved in schizophrenia, but the levels of PV protein and of individual PNN components, especially the carbohydrate moieties on proteoglycans to which WFA binds, are lower. Given the roles of PV neurons in regulating DLPFC microcircuits and of PNNs in regulating PV cellular physiology, the identified alterations in PV neurons and their PNNs could contribute to DLPFC dysfunction in schizophrenia.Neuropsychopharmacology advance online publication, 9 March 2016; doi:10.1038/npp.2016.24. |
| SCZ Keywords | schizophrenia, schizophrenic |