Expression of Interneuron Markers in the Dorsolateral Prefrontal Cortex of the Developing Human and in Schizophrenia

The Stanley Medical Research Institute, Chevy Chase Village, Maryland, United States
American Journal of Psychiatry (Impact Factor: 12.3). 11/2010; 167(12):1479-88. DOI: 10.1176/appi.ajp.2010.09060784
Source: PubMed


The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the γ-aminobutyric acid (GABA) inhibitory system shows protracted development, and GABA-ergic deficits are widely replicated in postmortem schizophrenia studies. The authors examined expression of several interneuron markers across postnatal human development and in schizophrenia to assess whether protracted development of certain interneuron subpopulations may be associated with a particular vulnerability in schizophrenia.
RNA was extracted postmortem from dorsolateral prefrontal cortex of individuals from age 6 weeks to 49 years (N=68) and from a cohort of normal comparison subjects and schizophrenia patients (N=74, 37 pairs). Expression levels of parvalbumin, cholecystokinin, somatostatin, neuropeptide Y, calretinin, calbindin, and vasoactive intestinal peptide were measured by quantitative reverse transcription-polymerase chain reaction. Changes in calretinin protein levels were examined by Western blot.
Interneuron marker genes followed one of three general expression profiles: either increasing (parvalbumin, cholecystokinin) or decreasing (somatostatin, calretinin, neuropeptide Y) in expression over postnatal life, with the most dramatic changes seen in the first few years before reaching a plateau; or increasing to peak expression in the toddler years before decreasing (calbindin, vasoactive intestinal peptide). mRNA expression of all genes, with the exception of calbindin (which increased), showed a reduction (8%-31%) in schizophrenia. Somatostatin showed the most dramatic reduction (31%) in schizophrenia.
It appears that a heterogeneous population of interneurons is implicated in schizophrenia. Further studies are needed to determine whether specific interneuron subpopulations are altered or whether common or distinct upstream pathways are responsible for interneuron deficits in schizophrenia.

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    • "Altered pre-and post-synaptic markers of cortical and hippocampal GABAergic neurotransmission are, in fact, among the most consistently observed abnormalities in developmental psychiatric disorders, most notably schizophrenia (Benes and Berretta, 2001; Volk and Lewis, 2013). Post-mortem studies conducted in schizophrenic patients report reduced expression levels of specific GABAergic interneuron markers, including parvalbumin and somatostatin (Hashimoto, Arion, et al., 2008; Morris et al., 2008; Fung et al., 2010; Konradi et al., 2011), along with deficient expression of various presynaptic regulators of GABA neurotransmission such as the 67 kDA isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD 67 ) and the GABA transporter 1 (Hashimoto, Bazmi, et al., 2008). These changes are further accompanied by altered levels of GABA A receptor subunits, including increased α2 subunits and decreased α1, α4, and α5 subunits in cortical layers of patients with schizophrenia (Hashimoto, Arion, et al., 2008; Hashimoto, Bazmi, et al., 2008; Duncan et al., 2010; Beneyto et al., 2011). "
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    ABSTRACT: Impaired γ-aminobutyric acid (GABA) signaling may contribute to the emergence of cognitive deficits and subcortical dopaminergic hyperactivity in patients with schizophrenia and related psychotic disorders. Against this background, it has been proposed that pharmacological interventions targeting GABAergic dysfunctions may prove useful in correcting such cognitive impairments and dopaminergic imbalances. Here, we explored possible beneficial effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH3, with partial selectivity at the α2, α3, and α5 subunits of the GABAA receptor in an immune-mediated neurodevelopmental disruption model. The model is based on prenatal administration of the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)] in mice, which is known to capture various GABAergic, dopamine-related, and cognitive abnormalities implicated in schizophrenia and related disorders. Real-time polymerase chain reaction analyses confirmed the expected alterations in GABAA receptor α subunit gene expression in the medial prefrontal cortices and ventral hippocampi of adult poly(I:C) offspring relative to control offspring. Systemic administration of SH-053-2'F-S-CH3 failed to normalize the poly(I:C)-induced deficits in working memory and social interaction, but instead impaired performance in these cognitive and behavioral domains both in control and poly(I:C) offspring. In contrast, SH-053-2'F-S-CH3 was highly effective in mitigating the poly(I:C)-induced amphetamine hypersensitivity phenotype without causing side effects in control offspring. Our preclinical data suggest that benzodiazepine-like positive allosteric modulators with activity at the α2, α3, and α5 subunits of the GABAA receptor may be particularly useful in correcting pathological overactivity of the dopaminergic system, but they may be ineffective in targeting multiple pathological domains that involve the co-existence of psychotic, social, and cognitive dysfunctions. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Schizophrenia Research 01/2015; 153(4). DOI:10.1093/ijnp/pyu055 · 3.92 Impact Factor
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    • "Furthermore, among individuals with schizophrenia, higher IL1β mRNA levels were associated poorer verbal fluency performance and reduced Broca's area volume. He and colleagues have shown that white matter interneurons are increased in schizophrenia (Joshi et al., 2012), whereas other studies showed that cortical interneurons are reduced (Fung et al., 2010). More recently, white matter interneurons were only increased in a subset of patients with high expression of inflammatory markers. "
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    ABSTRACT: The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5–9, 2014 and this year had as its emphasis, “Fostering Collaboration in Schizophrenia Research”. Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future.In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
    Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.08.032 · 3.92 Impact Factor
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    • "In a human post mortem study, mRNA expression of seven calcium binding proteins and neuropeptides expressed by GABAergic interneurons were examined in the dorsolateral PFC (DLPFC) of individuals from age 6 weeks to 49 years (Fung et al., 2010). Expression of parvalbumin (Chandelier and basket cells) and cholecystokinin (large basket cells) demonstrate a delayed increase, with levels peaking during the adolescent years, whereas other calcium binding proteins or neuropeptide expression either peak earlier in development or decrease slowly over the age span examined (in humans, Fung et al., 2010; in rats, Kawaguchi & Kondo, 2002). In contrast, GABA interneurons in the hippocampus generally have been found to obtain adult morphological characteristics early in life, prior to adolescence (in mice, Jiang et al., 2001). "
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    ABSTRACT: There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders.
    Pharmacology [?] Therapeutics 08/2014; DOI:10.1016/j.pharmthera.2014.03.001 · 9.72 Impact Factor
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Samantha Fung