Department of Neuropsychopharmacology and Hospital Pharmacy

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Email	pharmacy◎med.nagoya-u.ac.jp (Please send a message after replacing "◎" mark with "@" mark. )
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OUTLINE

The brain controls directly or indirectly all physiological activities, from heart rate to memory. Each brain function is regulated by specific neural circuits composed of neurons interconnected by synapses. A key feature of synapses is their activity-dependent plasticity. Our laboratory primarily investigates neuropsychiatric disorders and higher brain functions. Our research on neuropsychiatric disorders aims to elucidate the etiology and pathophysiology of conditions such as schizophrenia, drug addiction, and Alzheimer’s disease. In addition, our studies on higher brain functions focus on uncovering the molecular and cellular mechanisms underlying learning and memory, emotion, motivation, and decision-making.
Our laboratory also researches pharmacotherapy procedures and outcomes. Pharmacotherapy is often associated with adverse drug reactions, making safety management a critical component of clinical practice. Our research aims to improve the safety of pharmacotherapy by identifying risk factors for adverse events and optimizing patient-specific monitoring strategies, supportive care, and dosage regimens to prevent or mitigate toxicity.

RESEARCH PROJECTS

1. The neural circuits of motivation and decision-making

Decision-making is a key function in everyday life. The inability to make appropriate decisions or to anticipate the possible consequences of decisions can result in personal, social, and financial problems. Impaired decision-making is a symptom of several neuropsychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and drug dependence. Patients with anorexia, bulimia, and obesity also exhibit decision-making deficits on the Iowa gambling task, indicating that the reward system is impaired in compulsive food-related disorders. Impairment of decision-making in neuropsychiatric disorders is associated with an inability to make profitable long-term decisions that incorporate expectations of future outcomes. Impaired decision-making is therefore recognized as a core problem in neuropsychiatric disorders; however, the underlying neuronal mechanisms are largely unknown. To gain insights into these mechanisms and to develop successful treatments for these diseases, we examine impaired decision-making in animal models of neuropsychiatric disorders. We also investigate the neuronal mechanisms of motivation, which drives the initiation of actions (decision-making) based on internal desires.

2. Pathophysiological mechanisms of schizophrenia and the development of novel therapeutic drugs

Schizophrenia is a severe psychiatric disorder that typically emerges in late adolescence and early adulthood. It affects approximately 1% of the population and involves positive symptoms (such as hallucinations and delusions), negative symptoms (such as flat affect and social withdrawal), and cognitive dysfunction (such as deteriorations in working memory, executive function, and learning). The pathoetiology of schizophrenia is not fully understood because of its complexity and heterogeneity. However, copy-number variations in the ARHGAP10 gene, which encodes Rho GTPase activating protein 10, are associated with schizophrenia. We have explored the pathomechanism of schizophrenia using model mice that carry “double-hit” variations in the Arhgap10 gene (Arhgap10 S490P/NHEJ mice). These mice model the genetic variations found in a Japanese patient with schizophrenia and mimic the patient’s phenotype histologically and behaviorally. We have found that targeting RhoA/Rho-kinase signaling may provide new therapeutic approaches for the treatment of schizophrenia patients, including those with ARHGAP10 variations (Fig. 1). Furthermore, we have identified Twinfilin 1 as a downstream effector of reelin signaling via phosphoproteomic analysis, and demonstrated Twinfilin 1 phosphorylation to be a key component of reelin-mediated actin remodeling and dendritic spine development (Fig. 2).

Fig. 1. A Rho kinase inhibitor ameliorates cognitive deficits and spine formation abnormalities in Arhgap10 S490P/NHEJ mice. (Tanaka et al., Pharmacol Res, 2023;187: 106589, CC BY-NC ND)

Fig. 2. Phosphorylation of Twinfilin 1 (Twf1) contributes to Reelin-mediated actin remodeling and spine formation, and plays a role in learning and memory. (Dong et al., Pharmacol Res, 2025; 221:107986, CC BY-NC-ND)

3. Pathophysiological mechanisms of neurocognitive disorder

Neurodegenerative diseases, such as Alzheimer’s disease and frontotemporal dementia, are clinically characterized by impairments in cognitive and sensorimotor function and by neuropathological processes. These processes are commonly associated with age-related protein aggregation. Alzheimer’s disease is marked by the presence of extracellular senile plaques, composed of amyloid beta peptides, and intracellular neurofibrillary tangles, which consist of bundles of paired helical filaments of the microtubule-associated protein, Tau. The molecular mechanisms linking the aggregation of these proteins and neurodegeneration remain to be elucidated. To examine the mechanism of neurocognitive decline, we have found touchscreen-based tasks to be effective. We have used such tasks to assess cognitive impairment and to detect Alzheimer’s disease-associated behavioral impairments with high sensitivity at an early stage (Fig. 3). Moreover, we have demonstrated that specific genetic characteristics of glial cells may lead to abnormal behavior in an animal model of neurocognitive disorder.

Fig. 3. Development of a system for early detection of cognitive impairment in an Alzheimer’s disease mouse model.

4. Improving the safety of pharmacotherapy and evaluating the role of pharmacists in inter-professional collaboration

Pharmacotherapy is often associated with adverse drug reactions, making safety management a critical component of clinical practice. Our research aims to improve the safety of pharmacotherapy by identifying risk factors for adverse events and optimizing patient-specific monitoring strategies, supportive care, and dosage regimens to prevent or mitigate toxicity.

Given the substantial inter-individual variability in pharmacokinetics, we comprehensively evaluate drug absorption, distribution, metabolism, excretion, and drug–drug interactions. We use therapeutic drug monitoring and pharmacokinetic analyses, combined with population pharmacokinetic/pharmacodynamic modeling, to explore the relationships between drug exposure, efficacy, and adverse effects, thereby supporting individualized treatment.

Pharmacists play a central role in inter-professional healthcare teams by assessing pharmacotherapy from multiple perspectives and addressing clinical issues encountered in daily practice. We also objectively evaluate the impact of pharmacists’ clinical activities and collaborative practices. For example, pharmacist-led consultations prior to outpatient visits can reduce adverse events and improve treatment outcomes through proactive management and timely recommendations to physicians. Our work seeks to further advance safe, effective, and team-based pharmacotherapy.

BIBLIOGRAPHY