Selective expression of KCNS3 potassium channel α-subunit in parvalbumin-containing GABA neurons in the human prefrontal cortex

The cognitive deficits of schizophrenia appear to be associated with altered cortical GABA neurotransmission in the subsets of inhibitory neurons that express either parvalbumin (PV) or somatostatin (SST). Identification of molecular mechanisms that operate selectively in these neurons is essential for developing targeted therapeutic strategies that do not influence other cell types. Consequently, we sought to identify, in the human cortex, gene products that are expressed selectively by PV and/or SST neurons, and that might contribute to their distinctive functional properties. Based on previously reported expression patterns in the cortex of mice and humans, we selected four genes: KCNS3, LHX6, KCNAB1, and PPP1R2, encoding K+ channel Kv9.3 modulatory α-subunit, LIM homeobox protein 6, K+ channel Kvβ1 subunit, and protein phosphatase 1 regulatory subunit 2, respectively, and examined their colocalization with PV or SST mRNAs in the human prefrontal cortex using dual-label in situ hybridization with 35S- and digoxigenin-labeled antisense riboprobes. KCNS3 mRNA was detected in almost all PV neurons, but not in SST neurons, and PV mRNA was detected in >90% of KCNS3 mRNA-expressing neurons. LHX6 mRNA was detected in almost all PV and >90% of SST neurons, while among all LHX6 mRNA-expressing neurons 50% expressed PV mRNA and >44% expressed SST mRNA. KCNAB1 and PPP1R2 mRNAs were detected in much larger populations of cortical neurons than PV or SST neurons. These findings indicate that KCNS3 is a selective marker of PV neurons, whereas LHX6 is expressed by both PV and SST neurons. KCNS3 and LHX6 might be useful for characterizing cell-type specific molecular alterations of cortical GABA neurotransmission and for the development of novel treatments targeting PV and/or SST neurons in schizophrenia. © 2012 Georgiev et al

スコポラミン投与後の脳波変化 : 安静時および光刺激中の定量分析

取得学位：博士(医学), 学位番号：医博甲第1378号，学位授与年月日：平成11年6月30日,学位授与年：199

幼児用MEGによる未就学広汎性発達障害児の生理学的検討

金沢大学子どものこころの発達研究センターAutism spectrum disorders (ASD) appear in infancy and early childhood, causing delays or impairments in social interaction, communication, and a restricted range of interests. With recent developments in neuroimaging methods, the accumulated evidence suggests that aberrant brain connectivity reflect important aspects of network dysfunction associated with the pathophysiology of ASD. To gain insight into the development of this network dysfunction, it is necessary to study the pathophysiology in younger children with ASD, as aberrant development of white matter pathways may appear in infant stage. However, under conscious conditions, it has been challenging to measure brain functional connectivity in young children with ASD children using creditable methods as they are not always cooperative and persevering. We have recently reported the aberrant brain functional connectivity under conscious conditions in pre- school children with ASD. In our recent studies, we developed the child custom- sized MEG system in which sensors are as close to the whole head as possible for optimal recording even in young children, which otherwise would have been difficult with a conventional adult- sized MEG system. This is a unique and useful technique for young children that can provide measures of cortical neural activity on a millisecond timescale. By obtaining non- invasive measurements with a child custom- sized MEG, we have demonstrate an aberrant brain functional lateralization in conscious preschool children with ASD.最近の脳画像研究により，広汎性発達障害において，脳の側性化が定型発達者に比して乏しいことが報告されている。これらの所見は，脳の構造画像，脳血流の反応などにより報告されてきた。しかし，就学前の広汎性発達障害児童の覚醒状態脳機能の側性化については，これまでほとんど検討されていない。近年我々は，未就学の広汎性発達障害児と，定型発達児を対象に幼児用脳磁計（MEG）をもちいた脳機能測定を進めてきた。その結果，広汎性発達障害に特徴的ないくつかの所見が得られつつある。今回用いた幼児用MEGにおいては，従来の成人用MEGを幼児に行う場合に困難であった左右半球の脳機能測定を容易に行うことが可能となった。磁場の物理的性質から，半球間の機能の比較などを評価する点において，脳波に比べて妥当な方法で，さらに，MEGは電極の装着などの煩雑さがなく，母親の傍らで簡便に行うことが可能である点で，幼児には理想的な方法である

Anodal Transcranial Direct Current Stimulation Induces High Gamma-Band Activity in the Left Dorsolateral Prefrontal Cortex During a Working Memory Task: A Double-Blind, Randomized, Crossover Study

Transcranial direct current stimulation (tDCS) has been shown to have mixed effects on working memory (WM) capacity in healthy individuals. Different stimulation paradigms may account for these discrepancies, with certain features being favored. To determine the effect in the context of anodal tDCS, we investigated whether anodal tDCS induced cortical oscillatory changes during a WM task. Specifically, we tested whether anodal offline tDCS over the left prefrontal cortex (PFC) enhances WM capacity by modulating the oscillatory activity in the left dorsolateral PFC (DLPFC) using magnetoencephalography (MEG). This study employed a double-blind, randomized, crossover design, in which 24 healthy right-handed participants conducted MEG recordings during a 3-back task after administration of 2 mA tDCS or sham stimulation as a placebo. Our results showed that the effect of tDCS did not appear in the behavioral indices—WM accuracy (d′) or reaction time (RT). From the results of the time-frequency analysis, significant event-related synchronization (ERS) in the high-gamma band (82–84 Hz) of the left DLPFC was found under the tDCS condition; however, ERS was not correlated with WM capacity. Furthermore, we calculated the modulation index (MI), which indicates the strength of phase-amplitude coupling (PAC). tDCS significantly decreased MI of the left DLPFC, representing the theta-gamma PAC during the n-back task using color names as verbal stimuli. Our results suggest that although tDCS increased the gamma-band oscillation indicating greater neural activity in the left DLPFC, it did not lead to an improvement of WM capacity; this may be due to the inability of gamma-band oscillation to couple with the task-induced theta wave. WM capacity might not increase unless theta-gamma PAC is not enhanced by tDCS

CD38 and its role in oxytocin secretion and social behavior

Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase activity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism of CD38-dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38. This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. © 2011 Elsevier Inc

Neural responses to syllable-induced P1m and social impairment in children with autism spectrum disorder and typically developing Peers

In previous magnetoencephalography (MEG) studies, children with autism spectrum disorder (ASD) have been shown to respond differently to speech stimuli than typically developing (TD) children. Quantitative evaluation of this difference in responsiveness may support early diagnosis and intervention for ASD. The objective of this research is to investigate the relationship between syllable-induced P1m and social impairment in children with ASD and TD children. We analyzed 49 children with ASD aged 40–92 months and age-matched 26 TD children. We evaluated their social impairment by means of the Social Responsiveness Scale (SRS) and their intelligence ability using the Kaufman Assessment Battery for Children (K-ABC). Multiple regression analysis with SRS score as the dependent variable and syllable-induced P1m latency or intensity and intelligence ability as explanatory variables revealed that SRS score was associated with syllable-induced P1m latency in the left hemisphere only in the TD group and not in the ASD group. A second finding was that increased leftward-lateralization of intensity was correlated with higher SRS scores only in the ASD group. These results provide valuable insights but also highlight the intricate nature of neural mechanisms and their relationship with autistic traits

Association Between Magnetoencephalographic Interictal Epileptiform Discharge and Cognitive Function in Young Children With Typical Development and With Autism Spectrum Disorders

Electroencephalograms of individuals with autism spectrum disorders (ASD) show higher rates of interictal epileptiform discharges (IEDs), which are known to have an inverse association with cognitive function in typically developed (TD) children. Nevertheless, that phenomenon has not been investigated adequately in children with ASD. From university and affiliated hospitals, 163 TD children (84 male, 79 female, aged 32–89 months) and 107 children (85 male, 22 female, aged 36–98 months) with ASD without clinical seizure were recruited. We assessed their cognitive function using the Kaufman Assessment Battery for Children (K-ABC) and recorded 10 min of MEG. Original waveforms were visually inspected. Then a linear regression model was applied to evaluate the association between the IED frequency and level of their cognitive function. Significantly higher rates of IEDs were found in the ASD group than in the TD group. In the TD group, we found significant negative correlation between mental processing scale scores (MPS) and the IED frequency. However, for the ASD group, we found significant positive correlation between MPS scores and the IED frequency. In terms of the achievement scale, correlation was not significant in either group. Although we found a correlative rather than a causal effect, typically developed children with higher IED frequency might better be followed up carefully. Furthermore, for children with ASD without clinical seizure, clinicians might consider IEDs as less harmful than those observed in TD children