Ju-Chun Pei

Phenotypic characterization of C57BL/6J mice carrying the Disc1 gene from the 129S6/SvEv strain

Disruption of disrupted-in-schizophrenia 1 (DISC1), a candidate susceptibility gene for schizophrenia, was first identified in a large Scottish family in which many members suffered from various psychiatric disorders, including schizophrenia. To model the Scottish DISC1 truncation, we established a Disc1 mutant mouse line in which the 129S6/SvEv 25-bp deletion variant was transferred into the C57BL/6J strain by backcrossing. A battery of behavioral tasks was conducted to evaluate the basic behaviors and cognitive function of these mice. In heterozygote and homozygote Disc1 mutant (Het and Homo) mice, behavioral impairments were noted in working memory test which is thought to be mediated by the function of the medial prefrontal cortex (mPFC). The properties of mPFC neurons were characterized in both morphological and physiological aspects. The dendritic diameters were decreased in layer II/III mPFC pyramidal neurons of Het and Homo mice, whereas a significant reduction in spine density was observed in Homo mice. Neuronal excitability was declined in layer II/III mPFC pyramidal neurons of Het and Homo mice, yet increased transmitter release was identified in Homo mice. Thus, the structural and functional alterations of the mPFC in Het and Homo mice might account for their cognitive impairment. Since most of the gene knockout mice are generated from 129 substrain-derived embryonic stem cells, potential Disc1 deficiency should be considered.

Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits

Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1+/−, Nrg1+/−, and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1+/− and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1+/− mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Parkinsons disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.

Assessing Schizophrenia-relevant Cognitive and Social Deficits in Mice: A Selection of Mouse Behavioral Tasks and Potential Therapeutic Compounds

Schizophrenia and other psychiatric disorders are generally diagnosed based on a collection of symptoms defined by a combination of an individuals feelings, perceptions, and behaviors. Many of these disorders are characterized by specific cognitive and social deficits. Although it is nearly impossible to recapitulate the full phenotypic spectrum of schizophrenia in mice, mouse models play an indispensable role in understanding the pathogenesis of this disorder and the development of new therapeutics. Genetic mouse models of schizophrenia and mouse behavioral tests provide a feasible approach for elucidating causal relationships between susceptibility gene(s) and schizophrenia-related symptoms. There has been a proliferation of studies characterizing basic behavioral phenotypes in mice. Since there is no way to completely model human psychiatric symptoms in mice, the major role of behavioral tests is to provide insights into underlying affected circuitry and pathophysiology. Given that the recovery of cognitive and social abilities significantly benefits functional outcomes, there has been an increasing interest in characterizing cognitive and social functions in mutant mice; however, these functions are not easy to measure. In this review, a selection of conventional behavioral tasks was briefly described and three specific behavioral tasks aimed at characterizing social communication, attentional function, and choice behavior in mice were highlighted. The choice of specific behavioral tasks during experimental planning should take into consideration a variety of factors, including their validity, reliability, sensitivity, utility, and specificity. Based upon the hypothetical hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathways in the involvement of cognitive and social impairments in schizophrenia, three NMDAR-related compounds/drugs, D-serine, sarcosine, and D-cycloserine, are discussed as an example.

Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinsons disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.

Behavioral and cognitive characterizations of AKT1-NRG1 single and double mutant mice

mice showed much suppression of BBB permeability compared to wild-type mice. We also found Matrix metalloprotease-9 (MMP-9) as a possible candidate of substrate for KLK6. Immunoblot analysis revealed that activation of MMP-9 was inhibited in KLK6 KO mice with EAE. These results suggest that KLK6 plays a crucial role of the pathogenesis of EAE. Elucidation of KLK6mediated demyelination will be important in understanding the molecular mechanism of MS progression and KLK6 may be a possible therapeutic target for MS.

Effects of periadolescent exposure to methamphetamine on adult behavioral performances in male Akt1 deficient mice

Viral infection during neurodevelopment is involved in the etiology of psychiatric diseases including schizophrenia. There is a high prevalence of substance use disorder in first-episode schizophrenia. To examine whether the combination of a neonatal viral infection with an adolescent substance use affect on psychological function in adult, we subjected behavioral tests to adult C57/BL6J mice, which were treated with polyriboinosinicpolyribocytidylic acid (polyI:C; an inducer of strong innate immune responses) at a dose of 5mg/kg during neonatal period (postnatal day 2-6) and with phencyclidine (PCP) at a dose of 10mg/kg during adolescent period (postnatal day 35-41). We demonstrated that neonatal polyI:C treatment exacerbated PCP-induced behavioral phenotypes in sensitization in hyperlocomotion, impulsiveness in a cliff avoidance test, social deficit in a social interaction test and object recognition impairment in a novel object recognition test. These results suggest that neonatal polyI:C injection exacerbates PCP-treated behavioral phenotypes in adult.

An investigation of neonatal immune challenge in NRG1 mutant mice

P2-o18 Olanzapine treatment induces Olig2 cell proliferation in the hypothalamus with weight gain and enlarged fat tissues Takahira Yamauchi 1 , Kouko Tatsumi 2, Hiroaki Okuda 2, Manabu Makinodan 1, Daisuke Ikawa 1, Naoya Hirota 1, Hiroki Yoshino 1, Miyuki Sadamatsu 1, Toshifumi Kishimoto 1, Akio Wanaka 2 1 Dept Psychiatry, Univ of Nara Med, Kashihara, Nara 2 Dept Anatomy2, Univ of Nara Med, Kashihara, Nara

The regulatory role of Akt1 in dopamine dependent behavior in male and female mice

in the thalamocortical loops. Involvement of basal ganglia in absence seizures was not shown in mice models, and roles of basal ganglia in the SWD generation were not known in any animal models. To address these issues, we performed in vivo and in vitro experiments using tottering (tg) mice, a well established model of absence epilepsy. In vivo experiments showed the involvement of basal ganglia in the SWD generation. In vitro experiments in the subthalamic nucleus (STN) neurons showed the enhanced membrane excitability in tg mice. This enhancement seemed to result from the decrement of the HCN channel activity. Unilateral blockades of STN HCN channels of tg mice extended the mean duration of SWDs. The results suggested that the basal ganglia play a positive role in the SWD generation through the enhanced membrane excitability caused by decreased HCN channel activity in the STN.