Kazuyuki Fujihara

Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes

Decreased expression of the GABA synthetic enzyme glutamate decarboxylase 67 (GAD67) in a subset of GABAergic neurons, including parvalbumin (PV)-expressing neurons, has been observed in postmortem brain studies of schizophrenics and in animal models of schizophrenia. However, it is unclear whether and how the perturbations of GAD67-mediated GABA synthesis and signaling contribute to the pathogenesis of schizophrenia. To address this issue, we generated the mice lacking GAD67 primarily in PV neurons and characterized them with focus on schizophrenia-related parameters. We found that heterozygous mutant mice exhibited schizophrenia-related behavioral abnormalities such as deficits in prepulse inhibition, MK-801 sensitivity, and social memory. Furthermore, we observed reduced inhibitory synaptic transmission, altered properties of NMDA receptor-mediated synaptic responses in pyramidal neurons, and increased spine density in hippocampal CA1 apical dendrites, suggesting a possible link between GAD67 deficiency and disturbed glutamatergic excitatory synaptic functions in schizophrenia. Thus, our results indicate that the mice heterozygous for GAD67 deficiency primarily in PV neurons share several neurochemical and behavioral abnormalities with schizophrenia, offering a novel tool for addressing the underlying pathophysiology of schizophrenia.

Associations among parenting experiences during childhood and adolescence, hypothalamus‐pituitary‐adrenal axis hypoactivity, and hippocampal gray matter volume reduction in young adults

Recent human studies have indicated that adverse parenting experiences during childhood and adolescence are associated with adulthood hypothalamus‐pituitary‐adrenal (HPA) axis hypoactivity. Chronic HPA axis hypoactivity inhibits hippocampal gray matter (GM) development, as shown by animal studies. However, associations among adverse parenting experiences during childhood and adolescence, HPA axis activity, and brain development, particularly hippocampal development, are insufficiently investigated in humans. In this voxel‐based structural magnetic resonance imaging study, using a cross‐sectional design, we examined the associations among the scores of parental bonding instrument (PBI; a self‐report scale to rate the attitudes of parents during the first 16 years), cortisol response determined by the dexamethasone/corticotropin‐releasing hormone test, and regional or total hippocampal GM volume in forty healthy young adults with the following features: aged between 18 and 35 years, no cortisol hypersecretion in response to the dexamethasone test, no history of traumatic events, or no past or current conditions of significant medical illness or neuropsychiatric disorders. As a result, parental overprotection scores significantly negatively correlated with cortisol response. Additionally, a significant positive association was found between cortisol response and total or regional hippocampal GM volume. No significant association was observed between PBI scores and total or regional hippocampal GM volume. In conclusion, statistical associations were found between parental overprotection during childhood and adolescence and adulthood HPA axis hypoactivity, and between HPA axis hypoactivity and hippocampal GM volume reduction in healthy young adults, but no significant relationship was observed between any PBI scores and adulthood hippocampal GM volume. Hum Brain Mapp 33:2211–2223, 2012.

Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers

Cortical interneurons are classified into several subtypes that contribute to cortical oscillatory activity. Parvalbumin (PV)-expressing cells, a type of inhibitory interneuron, are involved in the gamma oscillations of local field potentials (LFPs). Under ketamine-xylazine anesthesia or sleep, mammalian cortical circuits exhibit slow oscillations in which the active-up state and silent-down state alternate at ~1 Hz. The up state is composed of various high-frequency oscillations, including gamma oscillations. However, it is unclear how PV cells and somatostatin (SOM) cells contribute to the slow oscillations and the high-frequency oscillations nested in the up state. To address these questions, we used mice lacking glutamate decarboxylase 67, primarily in PV cells (PV-GAD67 mice) or in SOM cells (SOM-GAD67 mice). We then compared LFPs between PV-GAD67 mice and SOM-GAD67 mice. PV cells target the proximal regions of pyramidal cells, whereas SOM cells are dendrite-preferring interneurons. We found that the up state was shortened in duration in the PV-GAD67 mice, but tended to be longer in SOM-GAD67 mice. Firing rate tended to increase in PV-GAD67 mice, but tended to decrease in SOM-GAD67 mice. We also found that delta oscillations tended to increase in SOM-GAD67 mice, but tended to decrease in PV-GAD67 mice. Current source density and wavelet analyses were performed to determine the depth profiles of various high-frequency oscillations. High gamma and ripple (60–200 Hz) power decreased in the neocortical upper layers specifically in PV-GAD67 mice, but not in SOM-GAD67. In addition, beta power (15–30 Hz) increased in the deep layers, specifically in PV-GAD67 mice. These results suggest that PV cells play important roles in persistence of the up state and in the balance between gamma and beta bands across cortical layers, whereas SOM and PV cells may make an asymmetric contribution to regulate up-state and delta oscillations.

Relationship of γ-aminobutyric acid and glutamate+glutamine concentrations in the perigenual anterior cingulate cortex with performance of Cambridge Gambling Task.

The anterior cingulate cortex (ACC), consisting of the perigenual ACC (pgACC) and mid-ACC (i.e., affective and cognitive areas, respectively), plays a significant role in the performance of gambling tasks, which are used to measure decision-making behavior under conditions of risk. Although recent neuroimaging studies have suggested that the γ-aminobutyric acid (GABA) concentration in the pgACC is associated with decision-making behavior, knowledge regarding the relationship of GABA concentrations in subdivisions of the ACC with gambling task performance is still limited. The aim of our magnetic resonance spectroscopy study is to investigate in 20 healthy males the relationship of concentrations of GABA and glutamate+glutamine (Glx) in the pgACC, mid-ACC, and occipital cortex (OC) with multiple indexes of decision-making behavior under conditions of risk, using the Cambridge Gambling Task (CGT). The GABA/creatine (Cr) ratio in the pgACC negatively correlated with delay aversion score, which corresponds to the impulsivity index. The Glx/Cr ratio in the pgACC negatively correlated with risk adjustment score, which is reported to reflect the ability to change the amount of the bet depending on the probability of winning or losing. The scores of CGT did not significantly correlate with the GABA/Cr or Glx/Cr ratio in the mid-ACC or OC. Results of this study suggest that in the pgACC, but not in the mid-ACC or OC, GABA and Glx concentrations play a distinct role in regulating impulsiveness and risk probability during decision-making behavior under conditions of risk, respectively.

The inhibition/excitation ratio related to task-induced oscillatory modulations during a working memory task: A multtimodal-imaging study using MEG and MRS

Detailed studies on the association between neural oscillations and the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been performed in vitro. In addition, recent functional magnetic resonance imaging studies have characterized these neurotransmitters in task-induced deactivation processes during a working memory (WM) task. However, few studies have investigated the relationship between these neurotransmitters and task-induced oscillatory changes in the human brain. Here, using combined magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS), we investigated the modulation of GABA and glutamate + glutamine (Glx) concentrations related to task-induced oscillations in neural activity during a WM task. We first acquired resting-state MRS and MEG data from 20 healthy male volunteers using the n-back task. Time-frequency analysis was employed to determine the power induced during the encoding and retention phases in perigenual anterior cingulate cortex (pg-ACC), mid-ACC, and occipital cortex (OC). Statistical analysis showed that increased WM load was associated with task-induced oscillatory modulations (TIOMs) of the theta-gamma band relative to the zero-back condition (TIOM0B) in each volume of interest during the encoding phase of the n-back task. The task-induced oscillatory modulations in the two-back condition relative to the zero-back condition (TIOM2B-0B) were negatively correlated with the percent rate change of the correct hit rate for 2B-0B, but positively correlated with GABA/Glx. The positive correlation between TIOM2B-0B and GABA/Glx during the WM task indicates the importance of the inhibition/excitation ratio. In particular, a low inhibition/excitation ratio is essential for the efficient inhibition of irrelevant neural activity, thus producing precise task performance.

P1-1-7. Relationship between gray matter volume of posterior cingulate cortex and frontal activation

Posterior cingulate cortex (PCC) is one of key nodes of default mode network. Recent studies have suggested that the connectivities between PCC and the other brain regions have important role in working memory performance. Therefore, we hypothesized that the local gray matter volume of PCC can affect the functions of frontal cortex. To address this issue, we acquired T1 weighted images for voxel-based morphometry, and measured time course of frontal oxygenated hemoglobin (Oxy-Hb) during letter verbal fluency task (VFT). Seventeen healthy volunteers were enrolled in the present study. We carried out the regression analysis between the gray matter concentration in PCC and the frontal oxy-Hb level during 0–60 s of VFT. This analysis found a significant cluster where the gray matter concentration is associated with frontal oxy-Hb level, even after adjustment of confounding factors including age and sex. Interestingly, there is no correlation between the gray matter concentration in frontal cortex and the frontal Oxy-Hb. These results suggest that gray matter volume of PCC rather than that of frontal cortex affects the extent of frontal activation during VFT. Our preliminary study may contribute to clarifying a role of PCC in the cognitive process.

P2-23. GABA predicts resting-state functional connectivity in cingulate cortex

Anterior cingulate cortex (ACC) is one of the key components of default mode network (DMN). Recent studies have shown that local concentrations of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in central nervous system, modulate activities of specific neuronal networks at rest. But the relationship between GABA level of ACC and the functional connectivity within DMN is largely unknown. In this study, we performed magnetic resonance spectroscopy (MRS) using MEGA-PRESS sequence to measure the amount of GABA in ACC and resting-state functional magnetic resonance imaging to evaluate intrinsic neuronal activity at rest in twenty-five healthy subjects. This experiment demonstrates that GABA/ Creatine (Cr) ratio is not correlated with the functional connectivity between ACC and other DMN regions. On the other hand, GABA/Cr ratio in ACC is significantly correlated with the functional connectivity between ACC and posterior-mid cingulate cortex (pMCC). These results suggests that local GABA level in ACC is a predictor of synchronized activity within cingulate cortex, rather than within DMN.

Association between Scale-Free Brain Dynamics and Behavioral Performance: Functional MRI Study in Resting State and Face Processing Task

The scale-free dynamics of human brain activity, characterized by an elaborate temporal structure with scale-free properties, can be quantified using the power-law exponent (PLE) as an index. Power laws are well documented in nature in general, particularly in the brain. Some previous fMRI studies have demonstrated a lower PLE during cognitive-task-evoked activity than during resting state activity. However, PLE modulation during cognitive-task-evoked activity and its relationship with an associated behavior remain unclear. In this functional fMRI study in the resting state and face processing + control task, we investigated PLE during both the resting state and task-evoked activities, as well as its relationship with behavior measured using mean reaction time (mRT) during the task. We found that (1) face discrimination-induced BOLD signal changes in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), amygdala, and fusiform face area; (2) PLE significantly decreased during task-evoked activity specifically in mPFC compared with resting state activity; (3) most importantly, in mPFC, mRT significantly negatively correlated with both resting state PLE and the resting-task PLE difference. These results may lead to a better understanding of the associations between task performance parameters (e.g., mRT) and the scale-free dynamics of spontaneous and task-evoked brain activities.

Parvalbumin-positive neuron-specific GAD67 knockout mice exhibit schizophrenia-like phenotypes

P3-s11 Gene expression analysis of hippocampi from alpha-CaMKII heterozygous knockout (KO) mice and Schnurri-2 KO mice using public microarray databases Hironori K. Nakamura 1 , Keizo Takao 2,3, Keiko Toyama 1,2, Tsuyoshi Takaji 4, Shunsuke Ishii 5, Tsuyoshi Miyakawa 1,2,3 1 Div. of Sys. Med. Sci., Inst. for Comprehensive Med. Sci., Fujita Health Univ., Toyoake, Japan 2 CREST, JST, Saitama, Japan 3 NIPS, Okazaki, Japan 4 Inst. for Develop. Res., Aichi Human Service Center, Kasugai, Japan 5 RIKEN Tsukuba Inst., Tsukuba, Japan

57. Comparison of prefrontal activation by low-frequency rTMS using two types of coil: A near-infrared spectroscopy study

lished. Our study aimed to investigate the relationships between pain and the stimulus duration when stimulus intensity is just sufficient to obtain the supramaximal stimulation. Fourteen normal subjects were enrolled for this evaluation. Tibial nerve was stimulated at the ankle with two out of three durations of 0.05, 0.2, and 1.0 ms. Six such combinations were tested in a random order, and subjects were asked to report which duration was more painful at each trial. Following two stimulus patterns were examined: pattern 1 was single supramaximal stimulation, and pattern 2 was a train of five maximal stimulations with 1 Hz, respectively. The stimulus duration with 0.2 ms caused minimum pain for both patterns, followed by 0.05 and 1.0 ms. This result indicate shorter duration is not always less painful. Furthermore, if we use 0.05 ms duration, the intensity necessary for supramaximal stimulation may easily exceed 100 mA for a pathological nerve with increased threshold. It is concluded that 0.2 ms duration, widely employed in Japan, is well appropriate.