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Lower Gene Expression for KCNS3 Potassium Channel Subunit in Parvalbumin-Containing Neurons in the Prefrontal Cortex in Schizophrenia
Danko Georgiev, M.D., Ph.D.; Dominique Arion, Ph.D.; John F. Enwright, Ph.D.; Mitsuru Kikuchi, M.D., Ph.D.; Yoshio Minabe, M.D., Ph.D.; John P. Corradi, Ph.D.; David A. Lewis, M.D.; Takanori Hashimoto, M.D., Ph.D.
Am J Psychiatry 2014;171:62-71. doi:10.1176/appi.ajp.2013.13040468
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Dr. Lewis receives investigator-initiated research support from Bristol-Myers Squibb, Curridium, and Pfizer and has served as a consultant for Bristol-Myers Squibb and Concert Pharmaceuticals. Dr. Hashimoto has served as a consultant for Ono Pharmaceutical. The other authors report no financial relationships with commercial interests.

Supported by the Japan Society for the Promotion of Science (Kakenhi grant 24791207 to Dr. Georgiev and grants 21390332, 25116509, and 25293247 to Dr. Hashimoto); a grant from SENSHIN Medical Research Foundation (to Dr. Hashimoto); a grant from Research Group for Schizophrenia (to Dr. Hashimoto); NIH grants MH043784 and MH084053 (to Dr. Lewis); and a grant from Bristol-Myers Squibb (to Dr. Lewis).

From the Department of Psychiatry and Neurobiology, Graduate School of Medical Science, and the Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan; the Departments of Psychiatry and Neuroscience, University of Pittsburgh, Pittsburgh; and the Department of Applied Genomics, Bristol-Myers Squibb, Wallingford, Conn.

Presented in part at the 34th annual meeting of the Japan Neuroscience Society, Yokohama, Japan, Sept. 14–17, 2011; and the 41st annual meeting of the Society for Neuroscience, Washington, D.C., November 12–16, 2011.

Address correspondence to Drs. Lewis and Hashimoto (lewisda@upmc.edu and takanori@med.kanazawa-u.ac.jp).

Copyright © 2014 by the American Psychiatric Association

Received April 09, 2013; Revised July 03, 2013; Accepted July 29, 2013.

Abstract

Objective  In schizophrenia, alterations in markers of cortical GABA neurotransmission are prominent in parvalbumin-containing neurons. Parvalbumin neurons selectively express KCNS3, the gene encoding the Kv9.3 potassium channel α-subunit. Kv9.3 subunits are present in voltage-gated potassium channels that contribute to the precise detection of coincident excitatory synaptic inputs to parvalbumin neurons. This distinctive feature of parvalbumin neurons appears important for the synchronization of cortical neural networks in γ-oscillations. Because impaired prefrontal cortical γ-oscillations are thought to underlie the cognitive impairments in schizophrenia, the authors investigated whether KCNS3 mRNA levels are altered in the prefrontal cortex of schizophrenia subjects.

Method  KCNS3 mRNA expression was evaluated by in situ hybridization in 22 matched pairs of schizophrenia and comparison subjects and by microarray analyses of pooled samples of individually dissected neurons that were labeled with Vicia villosa agglutinin (VVA), a parvalbumin neuron-selective marker, in a separate cohort of 14 pairs. Effects of chronic antipsychotic treatments on KCNS3 expression were tested in the prefrontal cortex of antipsychotic-exposed monkeys.

Results  By in situ hybridization, KCNS3 mRNA levels were 23% lower in schizophrenia subjects. At the cellular level, both KCNS3 mRNA-expressing neuron density and KCNS3 mRNA level per neuron were significantly lower. By microarray, KCNS3 mRNA levels were lower by 40% in VVA-labeled neurons from schizophrenia subjects. KCNS3 mRNA levels were not altered in antipsychotic-exposed monkeys.

Conclusions  These findings reveal lower KCNS3 expression in prefrontal cortical parvalbumin neurons in schizophrenia, providing a molecular basis for compromised detection of coincident synaptic inputs to parvalbumin neurons that could contribute to altered γ-oscillations and impaired cognition in schizophrenia.

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FIGURE 1. In Situ Hybridization Film Analysis of KCNS3 mRNA in Schizophrenia and Comparison Subjectsa

a In panel A, pseudocolored film autoradiographs of sections containing prefrontal cortex area 9 processed by in situ hybridization demonstrate lower KCNS3 mRNA levels in a schizophrenia subject relative to the matched comparison subject. The solid white line indicates the border between pia mater and layer 1, and the dotted line indicates the border between layer 6 and the white matter. The six cortical layers are identified on the left in each panel. Scale bar=1 mm. In panel B, average KCNS3 mRNA levels across gray matter of prefrontal cortex area 9 for schizophrenia subjects relative to matched comparison subjects are plotted for each pair. Green circles represent each subject pair. Data points to the right of the unity line indicate lower mRNA levels in the schizophrenia subject relative to the comparison subject and vice versa. Mean KCNS3 mRNA levels were 23% lower in schizophrenia subjects relative to matched comparison subjects. In panel C, KCNS3 mRNA expression levels in prefrontal cortex area 9 are plotted against age for schizophrenia subjects and comparison subjects. KCNS3 mRNA levels were significantly negatively correlated with age in comparison subjects, and the correlation fell short of significance in schizophrenia subjects. The regression line for schizophrenia subjects is parallel to and shifted downward from that for comparison subjects, suggesting that the decreased expression of KCNS3 mRNA is similar in magnitude across adult life.

FIGURE 2. KCNS3 mRNA Expression Analysis at the Cellular Levela

a Average numbers of KCNS3 mRNA-expressing neurons/mm2 (panel A) and average grain numbers per KCNS3 mRNA-expressing neuron (panel B) for schizophrenia subjects relative to matched comparison subjects are plotted for each pair. Green circles represent each subject pair. Data points to the right of the unity line indicate lower measures in the schizophrenia subject relative to the comparison subject and vice versa. In schizophrenia subjects, both the mean density of KCNS3 mRNA-expressing neurons and the mean grain number per KCNS3 mRNA-expressing neuron were lower (by 32% and 16%, respectively) relative to comparison subjects.

FIGURE 3. Microarray Analysis of KCNS3 and KCNB1 mRNA Levels in Vicia villosa Agglutinin (VVA)-Labeled Neurons in Schizophrenia and Comparison Subjectsa

a Representative photomicrographs demonstrate dual-fluorescence labeling using biotinylated VVA to detect perineuronal nets (panel A) and an antibody against the neuronal protein NeuN (panel B). In panel C, an overlay of panels A and B illustrates that only some neurons (arrowheads) are surrounded by perineuronal nets. Scale bar=10 μm. Log2-transformed microarray signals of KCNS3 (panel D) and KCNB1 (panel E) mRNAs for schizophrenia subjects relative to matched comparison subjects are plotted for each pair. Green circles represent each subject pair. Data points to the right of the unity line indicate lower mRNA signals in the schizophrenia subject relative to the comparison subject and vice versa. Mean KCNS3 and KCNB1 mRNA levels were decreased by 40% and 41%, respectively, in schizophrenia subjects relative to matched comparison subjects. In panel F, log2-transformed microarray signals for KCNS3 and KCNB1 mRNAs are plotted across 28 subjects, with blue and red circles representing comparison and schizophrenia subjects, respectively. Pearson’s correlation analysis revealed a significant correlation between KCNS3 and KCNB1 mRNA levels. In panel G, log2-tranformed signal ratios between schizophrenia and comparison subjects were calculated for both KCNS3 and KCNB1 mRNAs in each pair and plotted across 14 pairs. Green circles represent each subject pair. Pearson’s correlation analysis detected a trend toward correlated reductions of KCNS3 and KCNB1 mRNAs in schizophrenia.

FIGURE 4. Functional Implications of Reduced Kv2.1/Kv9.3 Channel Expression in Cortical Parvalbumin Neurons in Schizophreniaa

a In panel A, a schematic diagram illustrates a parvalbumin neuron (PV) that receives excitatory synapses from, and makes perisomatic inhibitory synapses on, neighboring pyramidal neurons (I–IV). In panel B, in unaffected subjects (left column), normal expression of Kv2.1/Kv9.3 heteromeric channels contributes to a normal level of assembled potassium channels in the cell membrane, which leads to fast excitatory postsynaptic potentials (EPSPs) in response to the firing of pyramidal neurons (I–IV). Because fast EPSPs summate during a short time window, the parvalbumin neuron fires only when it receives coincident excitatory inputs (i.e., EPSPs) from these pyramidal neurons (RMP=resting membrane potential). This ability of parvalbumin neurons to detect the synchronous firing of multiple pyramidal neurons, together with their perisomatic innervation of these pyramidal neurons, appears to be critical to the generation of γ-oscillations. In schizophrenia subjects (right column), lower levels of Kv2.1/Kv9.3 channels result in slower EPSPs, and thus even noncoincident EPSPs can sum to trigger action potentials in parvalbumin neurons. This alteration would compromise the detection of coincident EPSPs by parvalbumin neurons and impair the generation of γ-oscillations.

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TABLE 1.Characteristics of Two Nonoverlapping Subject Cohorts for In Situ Hybridization and Microarray Studies of KCNS3 mRNA Expression
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