Matej Markota

Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

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.

Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala

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.

Benzodiazepine Use in Older Adults: Dangers, Management, and Alternative Therapies

Several major medical and psychiatric organizations, including the American Geriatrics Society, advise against using benzodiazepines or nonbenzodiazepine hypnotics in older adults. Despite these recommendations, benzodiazepines continue to be massively prescribed to a group with the highest risk of serious adverse effects from these medications. This article summarizes legitimate reasons for prescribing benzodiazepines in the elderly, serious associated risks of prescribing them, particularly when not indicated, barriers physicians encounter in changing their prescription patterns, and evidence-based strategies on how to discontinue benzodiazepines in older patients. Although more research is needed, we propose several alternatives for treating insomnia and anxiety in older adults in primary care settings. These include nonpharmacological approaches such as sleep restriction-sleep compression therapy and cognitive behavioral therapy for anxiety or insomnia, and as well as alternative pharmacological agents.

Reduced Dopamine Transporter Expression in the Amygdala of Subjects Diagnosed With Schizophrenia

A disruption of dopaminergic transmission in the amygdala of subjects with schizophrenia was proposed as a main contributor to pathophysiological and clinical manifestations of this disorder. We tested the hypothesis that the expression of the dopamine transporter (DAT) is decreased in the amygdala of subjects with schizophrenia. In normal control, schizophrenic subjects and bipolar disorder subjects, we measured numerical density of axon varicosities immunoreactive (IR) for DAT in the lateral (LN), basal, accessory basal (ABN), and cortical (CO) nuclei and intercalated cell masses (ITCM) of the amygdala. Tyrosine hydroxylase (TH)-IR and dopamine beta-hydroxylase (DBH)-IR varicosities were measured to test for potential loss of varicosities and serotonin transporter (5HTT)-IR for involvement of the serotoninergic system. Among several potential confounding variables tested, particular emphasis was placed on exposure to therapeutic drugs. In schizophrenic subjects, DAT-IR varicosities were decreased in LN (P = .0002), ABN (P = .013), and CO (P = .0001) in comparison with controls, and in comparison with bipolar disorder subjects in LN (P = .004) and CO (P = .002). DBH-IR varicosities were decreased in ABN (P = .008) and ITCM (P = .017), compared with controls. TH- and 5HTT-IR varicosities were not altered. No changes were detected in bipolar disorder. Taken together with TH and DBH findings, reductions of DAT-IR varicosities point to decreased DAT expression in dopaminergic terminals in the amygdala of subjects with schizophrenia. This DAT decrease may disrupt dopamine uptake, leading to increased dopaminergic synaptic transmission and spillage into the extracellular space with activation of extrasynaptic dopamine receptors. Concurrent decrease of noradrenaline in the ABN may disrupt memory consolidation.

Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

BACKGROUND Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder. METHODS Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death was used to test associations with circadian rhythms. RESULTS SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p = .003) and SZ (Nt, p = .02). In normal control subjects, Nt of SST-IR neurons varied according to time of death. This pattern was altered in BD subjects, characterized by decreases of SST-IR neurons selectively in subjects with time of death corresponding to the day (6:00 am to 5:59 pm). Numbers of neuropeptide Y-IR neurons were not affected. CONCLUSIONS Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke’s R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10−13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

Rehospitalization to a child and adolescent psychiatry unit: Role of trauma and bullying

OBJECTIVE Psychiatric rehospitalizations results in a significant burden to patients, families, and health care systems. Understanding psychiatric rehospitalizations offers an opportunity to identify weaknesses in current systems of care. The objective of this study was to test the hypothesis that a history of trauma or ongoing bullying increases the risk of psychiatric rehospitalization. METHOD Retrospective cohort study of 366 individual patients (71% female) admitted to a pediatric psychiatry unit between 1/1/2015 and 12/31/2015. The primary outcome measure was rehospitalization to the same psychiatric hospital unit within one year of first discharge. Trauma was defined as having a history of Post-Traumatic Stress Disorder, Reactive Attachment Disorder, or a filed Suspected Abuse and Neglect of a Child report by the end of first hospitalization. Ongoing bullying was identified by medical record review. RESULTS History of trauma (Odds Ratio (OR) = 3.2, 95% Confidence Interval (CI) = 1.8-5.6, p < 0.0001) and ongoing bullying (OR = 2.2, CI = 1.2-3.9, p = 0.009) were significantly associated with increased rates of rehospitalizations. We controlled for the following covariates: Patient Health Questionnaire-9 Modified (PHQ-9M) score, gender, age, relative age, initial length of stay, disrupted family system, and sexual orientation/identity. CONCLUSION History of trauma or ongoing bullying are important risk factors for pediatric psychiatric rehospitalization.