Biology subjects

Ikesue, H.

Publications and source records attributed to Ikesue, H..

3 recordsLinked to original sources

bioRxiv2025

Distinct effects of nonselective Rho-kinase inhibitor fasudil and selective Rho-kinase 2 inhibitor KD025 on serotonin and dopamine release in the nucleus accumbens of mice

Recent studies have indicated that the Rho GTPase family and Rho-kinases are associated with psychiatric diseases, such as schizophrenia. Rho-kinases have two subtypes, Rho-kinases 1 and 2 that regulate actin dynamics and mediate neurite outgrowth, spine morphology in neurons, and neurotransmitter release in vitro and ex vivo. However, the precise role of Rho-kinases in neurotransmitter release in vivo remains unclear. To clarify the role of Rho-kinases 1 and 2 in serotonin and dopamine release in the nucleus accumbens (NAc) of mice in vivo, we investigated the effect of a nonselective Rho-kinase inhibitor, fasudil, and a selective Rho-kinase 2 inhibitor, KD025, using an in vivo microdialysis technique. Fasudil perfusion (1-20 M) into the NAc increased the basal extracellular serotonin level but did not affect dopamine levels, whereas KD025 (10-20 M) had little effect on basal serotonin and dopamine levels. Notably, fasudil perfusion into the NAc suppressed depolarization-induced serotonin and dopamine release in a dose-dependent manner, whereas KD025 selectively suppressed depolarization-induced serotonin release. Our results suggested that Rho-kinases 1 and 2 are associated with dopamine and serotonin release, respectively, and that both may have significant but distinct roles in the regulation of serotonin and dopamine release in the NAc.

neuroscience↗

bioRxiv2025

Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic Reln deletion

Reelin is an essential extracellular matrix glycoprotein involved in the formation of cortical layers and has been associated with several neuropsychiatric conditions, such as schizophrenia (SCZ). To explore its role in brain function and its potential involvement in SCZ, we developed a Reln heterozygous deletion (Relndel/+) mouse model that mimics a genetic deletion observed in a Japanese patient with SCZ. In previous studies, we demonstrated that Relndel/+ mice exhibit cognitive impairments in a visual discrimination test. Here, we found that Relndel/+ mice displayed impairments in social novelty recognition, while social preference remained intact. Immunohistochemical analyses revealed a significant decrease in the numbers of calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic pyramidal neurons, gamma-aminobutyric acid (GABA)-ergic interneurons, and parvalbumin (PV)-positive interneurons in the medial prefrontal cortex (mPFC) of Relndel/+ mice. Furthermore, Relndel/+ mice exhibited significant deficits in excitatory spine density and morphology, as well as a decrease number of PV boutons in the mPFC compared to wild-type (WT) mice. Finally, we demonstrated that injection of AAV-R36-Myc virus into the mPFC can improve social novelty impairments in Relndel/+ mice, but no effects on WT control. These findings indicate that Relndel/+ mice could be a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Futhermore, our results with AAV-R36-Myc also suggest the therapeutic potential of Reelin replacement, warranting further investigation as a possible treatment strategy for SCZ. HighlightsO_LIReelin deficiency disrupts social novelty, but not social preference, in Relndel/+ mice C_LIO_LIRelndel/+ mice serve as a novel model to investigate impairments of neuronal mechanisms on schizophrenia C_LIO_LIAAV-R36-myc injection rescues social novelty deficits in Relndel/+ mice C_LIO_LIReelin replacement therapy is a potential treatment for schizophrenia C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=143 HEIGHT=200 SRC="FIGDIR/small/666057v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1f4921aorg.highwire.dtl.DTLVardef@1a41b33org.highwire.dtl.DTLVardef@f5f2bcorg.highwire.dtl.DTLVardef@1134d8d_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2025

Twinfilin-1 phosphorylation in reelin signaling regulates actin dynamics and spine development

Reelin is an extracellular glycoprotein essential for neuronal migration, spine development, and synaptic plasticity. Impaired reelin signaling is linked to neurological disorders, including schizophrenia and autism. While reelin mutant (reeler) mice exhibit behavioral deficits associated with impaired spine formation, the underlying molecular mechanisms remain unclear. We identified Twinfilin-1 (Twf1) as a downstream effector of reelin signaling via phosphoproteomic analysis, based on its reduced tyrosine phosphorylation in reeler mice. We found that Src regulated Twf1 phosphorylation at tyrosine 309, and reelin stimulation increased Twf1 phosphorylation in neurons, an effect blocked by the Src inhibitor PP2. A phospho-resistant Twf1 mutant (Twf1 Y309F) showed reduced capping protein binding and a lower F/G-actin ratio. Twf1Y309F mice exhibited cognitive deficits, reduced spine density, smaller spine head size, and a decreased F/G-actin ratio in synaptosomes. These findings highlight Twf1 phosphorylation as a key component of reelin signaling involved in actin remodeling and spine development.

neuroscience↗