Localization of truncated TrkB and co-expression with full-length TrkB in the cerebral cortex of adult mice.

Brain-derived neurotrophic factor (BDNF), one of the neurotrophins, and its specific receptor TrkB, are abundantly distributed in the central nervous system (CNS) and have a variety of biological effects, such as neural survival, neurite elongation, neural differentiation, and enhancing synaptic functions. Currently, there are two TrkB subtypes: full-length TrkB (TrkB-FL), which has a tyrosine kinase in the intracellular domain, and TrkB-T1, which is a tyrosine kinase-deficient form. While TrkB-FL is a typical tyrosine kinase receptor, TrkB-T1 is a main form expressed in the CNS of adult mammals, but its function is unknown. In this study, we performed fluorescent staining of the cerebral cortex of adult mice, by using TrkB-T1 antiserum and various antibodies of marker molecules for neurons and glial cells. We found that TrkB-T1 was expressed not only in neurons but also in astrocytes. In contrast, little expression of TrkB-T1 was found in oligodendrocytes and microglia. TrkB-T1 was expressed in almost all of the cells expressing TrkB-FL, indicating the direct interaction between TrkB subtypes. These findings suggest that a part of various functions of BDNF-TrkB signaling might be due to the interaction and cellular localization of TrkB subtypes in the cerebral cortex.

Change of hypothalamic adult neurogenesis in mice by chronic treatment of fluoxetine.

OBJECTIVE: More than half of patients with depression display eating disorders, such as bulimia nervosa and anorexia nervosa. Feeding centers are located in the hypothalamus, and hypothalamic adult neurogenesis has an important role in feeding and energy balance. Antidepressants, which can regulate adult neurogenesis in the hippocampus, olfactory bulb, and neocortex, are used for eating disorders, but it is unclear whether antidepressants change hypothalamic adult neurogenesis. In this study, we used immunohistological analysis to assess effects of the antidepressant fluoxetine (FLX) on hypothalamic adult neurogenesis of adult mice. RESULTS: Expressions of the proliferating cell marker, Ki67, and the neural stem cell marker, nestin, were significantly decreased in the hypothalamus by FLX. As regard to postmitotic cells, the number of the neural marker, NeuN, positive cells was significantly upregulated by FLX, but that of the astrocytic marker, S100B, positive cells was significantly reduced by FLX. The number of the oligodendrocyte marker, Olig2, positive cells was not changed by FLX. Interestingly, FLX treatment did not affect the total number of newly generated cells in the hypothalamus, comparing that in controls. These results suggest that FLX treatment influence hypothalamic adult neurogenesis and shift the balance between the numbers of neurons and astrocytes under studied conditions.

Effects of leptin on proliferation of astrocyte- and tanycyte-like neural stem cells in the adult mouse medulla oblongata.

Astrocyte- and tanycyte-like neural stem cells (NSCs) were recently detected in the area postrema (AP) and central canal (CC) of the adult medulla oblongata, respectively. The present study aimed to examine dynamical behaviors of the astrocyte- and tanycyte-like NSCs of the mouse medulla oblongata to leptin. The neurosphere assay identified astrocytes in the AP and tanycytes in the CC as NSCs based on their self-renewing neurospherogenic potential. Both NSCs in neurosphere cultures were multipotent cells that generate astrocytes, oligodendrocytes, and neurons. Astrocyte-like NSCs actively proliferated and tanycyte-like NSCs were quiescent under physiologically-relevant in vivo conditions. Chronic leptin treatment promoted proliferation of astrocyte-like NSCs in the AP both in vitro and in vivo. Leptin receptors were expressed in astrocyte-like, but not tanycyte-like NSCs. Food deprivation significantly diminished proliferation of astrocyte-like NSCs. Therefore, the present study indicates that proliferation of astrocyte-like, but not tanycyte-like NSCs is regulated by nutritional conditions.

Predictors of increase in pacing threshold after transcatheter pacing system implantation due to micro-dislodgement.

BACKGROUND: Achieving a favorable pacing threshold with a Micra transcatheter pacing system (Micra-TPS) is needed to reduce battery depletion. In some cases, the threshold increases shortly after the device is implanted, and a higher pacing threshold may be required. This study aims to identify the causes and predictors of the increase in pacing threshold observed shortly after Micra-TPS implantation. METHODS: The study included 64 consecutive patients who underwent Micra-TPS implantation between 2017 and 2020. The patients were divided into two groups depending on their pacing threshold: the increased pacing threshold (IPT) group (threshold increased by ≥0.5 V/0.24 ms within 1 month of implantation) and the stable pacing threshold (SPT) group. RESULTS: Excluding four patients who could not be followed up, of the 60 remaining patients, nine (15%) were in the IPT group and 51 (85%) were in the SPT group. The IPT group had significantly lower implant impedance values and higher implant thresholds than the SPT group (582 ± 59 vs 755 ± 167 Ω [P < .001] and 1.29 ± 0.87 vs 0.71 ± 0.40 V/0.24 ms [P = .014]). Implant impedance and threshold may serve as predictors of a threshold increase after implantation (area under the curve: 0.737-0.943 and 0.586-0.926, respectively). CONCLUSIONS: An IPT was noted shortly after Micra-TPS implantation owing to micro-dislodgement because of insufficient anchoring of the device to the myocardium. Impedance >660 Ω and threshold <1.0 V/0.24 ms may predict an increase in pacing threshold.

Dopamine as a growth differentiation factor in the mammalian brain.

The catecholamine, dopamine, plays an important role in the central nervous system of mammals, including executive functions, motor control, motivation, arousal, reinforcement, and reward. Dysfunctions of the dopaminergic system lead to diseases of the brains, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. In addition to its fundamental role as a neurotransmitter, there is evidence for a role as a growth differentiation factor during development. Recent studies suggest that dopamine regulates the development of γ-aminobutyric acidergic interneurons of the cerebral cortex. Moreover, in adult brains, dopamine increases the production of new neurons in the hippocampus, suggesting the promoting effect of dopamine on proliferation and differentiation of neural stem cells and progenitor cells in the adult brains. In this mini-review, I center my attention on dopaminergic functions in the cortical interneurons during development and further discuss cell therapy against neurodegenerative diseases.

Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis.

It is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call "dematuration," in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer's disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases.

Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset.

The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders. Chronic FLX treatment reportedly induces cellular responses in the brain, including increased adult hippocampal and cortical neurogenesis and reversal of neuron maturation in the hippocampus, amygdala, and cortex. However, because most previous studies have used rodent models, it remains unclear whether these FLX-induced changes occur in the primate brain. To evaluate the effects of FLX in the primate brain, we used immunohistological methods to assess neurogenesis and the expression of neuronal maturity markers following chronic FLX treatment (3 mg/kg/day for 4 weeks) in adult marmosets (n = 3 per group). We found increased expression of doublecortin and calretinin, markers of immature neurons, in the hippocampal dentate gyrus of FLX-treated marmosets. Further, FLX treatment reduced parvalbumin expression and the number of neurons with perineuronal nets, which indicate mature fast-spiking interneurons, in the hippocampus, but not in the amygdala or cerebral cortex. We also found that FLX treatment increased the generation of cortical interneurons; however, significant up-regulation of adult hippocampal neurogenesis was not observed in FLX-treated marmosets. These results suggest that dematuration of hippocampal neurons and increased cortical neurogenesis may play roles in FLX-induced effects and/or side effects. Our results are consistent with those of previous studies showing hippocampal dematuration and increased cortical neurogenesis in FLX-treated rodents. In contrast, FLX did not affect hippocampal neurogenesis or dematuration of interneurons in the amygdala and cerebral cortex.

Catheter Ablation of Refractory Ventricular Fibrillation Storm After Myocardial Infarction.

BACKGROUND: Ventricular fibrillation (VF) storm after myocardial infarction (MI) is a life-threatening condition that necessitates multiple defibrillations. Catheter ablation is a potentially effective treatment strategy for VF storm refractory to optimal medical treatment. However, its impact on patient survival has not been verified in a large population. METHODS: We conducted a multicenter, retrospective observational study involving consecutive patients who underwent catheter ablation of post-MI refractory VF storm without preceding monomorphic ventricular tachycardia. The target of ablation was the Purkinje-related ventricular extrasystoles triggering VF. The primary outcome was in-hospital and long-term mortalities. Univariate logistic regression and Cox proportional-hazards analysis were used to evaluate clinical characteristics associated with in-hospital and long-term mortalities, respectively. RESULTS: One hundred ten patients were enrolled (age, 65±11years; 92 men; left ventricular ejection fraction, 31±10%). VF storm occurred at the acute phase of MI (4.5±2.5 days after the onset of MI during the index hospitalization for MI) in 43 patients (39%), the subacute phase (>1 week) in 48 (44%), and the remote phase (>6 months) in 19 (17%). The focal triggers were found to originate from the scar border zone in 88 patients (80%). During in-hospital stay after ablation, VF storm subsided in 92 patients (84%). Overall, 30 (27%) in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality (odds ratio for each 1-day increase, 1.11 [95% CI, 1.03-1.20]; P=0.008). During follow-up after discharge from hospital, only 1 patient developed recurrent VF storm. However, 29 patients (36%) died, with a median survival time of 2.2 years (interquartile range, 1.2-5.5 years). Long-term mortality was associated with left ventricular ejection fraction <30% (hazard ratio, 2.54 [95% CI, 1.21-5.32]; P=0.014), New York Heart Association class ≥III (hazard ratio, 2.68 [95% CI, 1.16-6.19]; P=0.021), a history of atrial fibrillation (hazard ratio, 3.89 [95% CI, 1.42-10.67]; P=0.008), and chronic kidney disease (hazard ratio, 2.74 [95% CI, 1.15-6.49]; P=0.023). CONCLUSIONS: In patients with MI presenting with focally triggered VF storm, catheter ablation of culprit triggers is lifesaving and appears to be associated with short- and long-term freedom from recurrent VF storm. Mortality over the long-term follow-up is associated with the severity of underlying cardiovascular disease and comorbidities in this specific patient population.

Dopamine stimulates differentiation and migration of cortical interneurons.

Cortical GABAergic interneurons originate and migrate tangentially from the medial ganglionic eminence (MGE), but its mechanism remains unknown. In this study, we show that dopamine (DA) stimulates the differentiation and migration of cortical interneurons derived from MGE cells. Using immunohistochemistry for the DA marker, tyrosine hydroxylase (TH), TH positive axons enter the MGE by E12.5. In E11.5 MGE primary cultures, DA enhances the expression of cortical interneuron marker proteins, such as GAD67 and neuropilin1, via D1 receptor, and also up-regulates D2 receptor. In E14.5 organotypic slice cultures, the migration of MGE cells is occurred in a D2 receptor-dependent manner, whose stimulation increased the synthesis of neurotrophins, in E11.5 MGE primary cultures. Furthermore, TH neurons-depletion by 6-hydroxydopamine treatments led to a significant reduction of cortical calbindin positive cells in the cerebral cortex, compared with the controls. Therefore, these results suggest that DA can stimulate the differentiation and migration of cortical interneurons.

Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex.

AIMS: The molecular and cellular mechanisms underlying the antidepressant effects of fluoxetine in the brain are not fully understood. Emerging evidence has led to the hypothesis that chronic fluoxetine treatment induces dematuration of certain types of mature neurons in rodents. These studies have focused on the properties of typical molecular and/or electrophysiological markers for neuronal maturation. Nevertheless, it remains unknown whether dematuration-related phenomena are present at the genome-wide gene expression level. METHODS: Based on the aforementioned hypothesis, we directly compared transcriptome data between fluoxetine-treated adult mice and those of naive infants in the hippocampus and medial prefrontal cortex (mPFC) to assess similarities and/or differences. We further investigated whether fluoxetine treatment caused dematuration in these brain regions in a hypothesis-free manner using a weighted gene co-expression network analysis (WGCNA). RESULTS: Gene expression patterns in fluoxetine-treated mice resembled those in infants in the mPFC and, to a large extent, in the hippocampus. The gene expression patterns of fluoxetine-treated adult mice were more similar to those of approximately 2-week-old infants than those of older mice. WGCNA confirmed that fluoxetine treatment was associated with maturation abnormalities, particularly in the hippocampus, and highlighted respective co-expression modules for maturity and immaturity marker genes in the hippocampus in response to fluoxetine treatment. CONCLUSIONS: Our results strongly support the hypothesis that chronic fluoxetine treatment induces dematuration in the adult mouse brain from a transcriptomic standpoint. Detection of discrete transcriptomic regulatory networks related to fluoxetine treatment may help to further elucidate the mechanisms of antidepressant action.

[A Case of Malignant Peritoneal Mesothelioma Treated with Cisplatin and Pemetrexed].

A 65-year-old man was admitted to our hospital complaining of general malaise, anorexia and weight loss. A computed tomography(CT)scan showed massive ascites and multiple peritoneal masses. Although adenocarcinoma was suspected based on the cytology of the ascites, we were unable to determine the site of origin. We next performed a laparoscopy and a biopsy of the tumor on the omentum. The laparoscopy showed small, white, hard nodules that were disseminated throughout the abdominalcavity, and histologicaldiagnosis confirmed malignant peritonealmesothel ioma. The patient was administered chemotherapeutic treatment of cisplatin and pemetrexed. After treatment, the ascites decreased; however, tumor regression was not observed. The patient's performance status gradually decreased, and he died on hospital day 104. Prognosis of malignant peritoneal mesothelioma remains poor, and malignant peritoneal mesothelioma should be considered when diagnosing peritoneal tumors.

Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability.

Accumulating evidence suggests that subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/pathophysiology of schizophrenia and intellectual disability. Previously, we proposed mice lacking Schnurri-2 (Shn2; also called major histocompatibility complex [MHC]-binding protein 2 [MBP-2], or human immunodeficiency virus type I enhancer binding protein 2 [HIVEP2]) as a schizophrenia and intellectual disability model with mild chronic inflammation. In the mutants' brains, there are increases in C4b and C1q genes, which are considered to mediate synapse elimination during postnatal development. However, morphological properties of subcellular-scale structures such as dendritic spine in Shn2 knockout (KO) mice remain unknown. In this study, we conducted three-dimensional morphological analyses in subcellular-scale structures in dentate gyrus granule cells of Shn2 KO mice by serial block-face scanning electron microscopy. Shn2 KO mice showed immature dendritic spine morphology characterized by increases in spine length and decreases in spine diameter. There was a non-significant tendency toward decrease in spine density of Shn2 KO mice over wild-type mice, and spine volume was indistinguishable between genotypes. Shn2 KO mice exhibited a significant reduction in GluR1 expression and a nominally significant decrease in SV2 expression, while PSD95 expression had a non-significant tendency to decrease in Shn2 KO mice. There were significant decreases in dendrite diameter, nuclear volume, and the number of constricted mitochondria in the mutants. Additionally, neuronal density was elevated in Shn2 KO mice. These results suggest that Shn2 KO mice serve as a unique tool for investigating morphological abnormalities of subcellular-scale structures in schizophrenia, intellectual disability, and its related disorders.

Population dynamics of neural progenitor cells during aging in the cerebral cortex.

Recent studies indicate that adult neurogenesis occurs in the cerebral cortex of rodents. Neural progenitor cells (NPCs) have been found in the adult cerebral cortex. These cells are expected to be regulated by various stimuli, including environmental enrichment, exercise, learning, and stress. However, it is unclear what stimuli can regulate cortical NPCs. In this study, we examined whether aging has an impact on population dynamics of NPCs in the murine cerebral cortex, using immunohistological staining for NPCs. The density of NPCs was kept from 5- to 12-month-old, dramatically decreased at 17-month-old, and thereafter maintained the same level until 24-month-old. Comparing the densities of NPCs in the cortical areas, such as the cingulate, primary motor, primary somatosensory, and insular cortices, we found that the degrees of decreased densities of NPCs in the cingulate and insular cortices were significantly smaller than those in the primary motor and somatosensory cortices. NPCs in aged cortex produced new neurons by ischemia. These results indicate that in aged mice, NPCs exist and produce new neurons in the cerebral cortex. Additionally, the extent of reduction of the density of NPCs in the cortices with higher cognitive functions may be less than that in the primary motor and somatosensory cortices.

BDNF pro-peptide: a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing.

Most growth factors are initially synthesized as precursors and it was cleaved into bioactive mature domain and pro-domain. However, compared with the expression and function of bioactive mature domain, the biological role of the pro-domain is poorly understood. Unexpectedly, we found that the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which is well-known neurotrophic factor in brain, has a potential ability to facilitate hippocampal long-term depression. Furthermore, a BDNF polymorphism Val66Met, which substitute valine into methionine at 66 amino acid, impacted the biological activity of the BDNF pro-peptide. We lastly discuss the possible roles of BDNF and its pro-peptide in the generation of neural stem cells and progress of ischemia.

Accelerated discovery of cathode materials with prolonged cycle life for lithium-ion battery.

Large-scale battery systems are essential for efficiently utilizing renewable energy power sources from solar and wind, which can generate electricity only intermittently. The use of lithium-ion batteries to store the generated energy is one solution. A long cycle life is critical for lithium-ion battery when used in these applications; this is different from portable devices which require 1,000 cycles at most. Here we demonstrate a novel co-substituted lithium iron phosphate cathode with estimated 70%-capacity retention of 25,000 cycles. This is found by exploring a wide chemical compositional space using density functional theory calculations. Relative volume change of a compound between fully lithiated and delithiated conditions is used as the descriptor for the cycle life. On the basis of the results of the screening, synthesis of selected materials is targeted. Single-phase samples with the required chemical composition are successfully made by an epoxide-mediated sol-gel method. The optimized materials show excellent cycle-life performance as lithium-ion battery cathodes.

Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia.

BACKGROUND: Schizophrenia, a severe psychiatric disorder, has a lifetime prevalence of 1%. The exact mechanisms underlying this disorder remain unknown, though theories abound. Recent studies suggest that particular cell types and biological processes in the schizophrenic cortex have a pseudo-immature status in which the molecular properties partially resemble those in the normal immature brain. However, genome-wide gene expression patterns in the brains of patients with schizophrenia and those of normal infants have not been directly compared. Here, we show that the gene expression patterns in the schizophrenic prefrontal cortex (PFC) resemble those in the juvenile PFC. RESULTS: We conducted a gene expression meta-analysis in which, using microarray data derived from different studies, altered expression patterns in the dorsolateral PFC (DLFC) of patients with schizophrenia were compared with those in the DLFC of developing normal human brains, revealing a striking similarity. The results were replicated in a second DLFC data set and a medial PFC (MFC) data set. We also found that about half of the genes representing the transcriptomic immaturity of the schizophrenic PFC were developmentally regulated in fast-spiking interneurons, astrocytes, and oligodendrocytes. Furthermore, to test whether medications, which often confound the results of postmortem analyses, affect on the juvenile-like gene expressions in the schizophrenic PFC, we compared the gene expression patterns showing transcriptomic immaturity in the schizophrenic PFC with those in the PFC of rodents treated with antipsychotic drugs. The results showed no apparent similarities between the two conditions, suggesting that the juvenile-like gene expression patterns observed in the schizophrenic PFC could not be accounted for by medication effects. Moreover, the developing human PFC showed a gene expression pattern similar to that of the PFC of naive Schnurri-2 knockout mice, an animal model of schizophrenia with good face and construct validity. This result also supports the idea that the transcriptomic immaturity of the schizophrenic PFC is not due to medication effects. CONCLUSIONS: Collectively, our results provide evidence that pseudo-immaturity of the PFC resembling juvenile PFC may be an endophenotype of schizophrenia.

Hippocampal neurogenesis regulates forgetting during adulthood and infancy.

Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury.

BACKGROUND: It is not clear what kind of drug is appropriate to heal NSAID-induced enteropathy. Several reports showed the preventive effect of prostaglandin analogue or inducer using healthy subjects who took NSAIDs. However there was no report for healing effect and for patients. The aim of this study was to evaluate the healing effect of rebamipide in patients with NSAIDs-induced enteropathy. In addition, we evaluated for nutritional parameter. METHODS: This study was conducted as a randomized, double-blinded, placebo-controlled, multicenter trial. Study protocol was approved by each hospital's ethical committees. Patients with LDA and/or NSAID more than 3 months were enrolled. Patients with enteropathy were divided into the placebo and the rebamipide groups. Rebamipide 100 mg three times daily was administered during 4 weeks. Capsule endoscopies were performed at 0 and 4 week. The number of small intestinal ulcer and erosion were evaluated. Total protein was analyzed as nutritional parameter. RESULTS: Sixty one participants were completed this study. Change in number of small intestinal erosion in the rebamipide group was -2.5 ± 3.4, and 2.1 ± 3.9 in the placebo group (P < 0.0001). Change in number of small intestinal ulcer in the rebamipide group was -0.5 ± 1.6, and 0.1 ± 0.7 in the placebo group (P = 0.024). Change in serum total protein levels in the rebamipide group was 0.06 ± 0.36, and -0.27 ± 0.34 in the placebo group (P = 0.0005). CONCLUSIONS: Rebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo, but the improvement of nutritional condition. These results showed a tentative therapeutical strategy for chronic NSAIDs users.

In vivo evaluation of cellular activity in αCaMKII heterozygous knockout mice using manganese-enhanced magnetic resonance imaging (MEMRI).

The alpha-calcium/calmodulin-dependent protein kinase II (αCaMKII) is a serine/threonine protein kinase predominantly expressed in the forebrain, especially in the postsynaptic density, and plays a key role in synaptic plasticity, learning and memory. αCaMKII heterozygous knockout (HKO) mice exhibit abnormal emotional and aggressive behaviors and cognitive impairments and have been proposed as an animal model of psychiatric illness. Our previous studies have shown that the expression of immediate early genes (IEGs) after exposure to electric foot shock or after performing a working memory task is decreased in the hippocampus, central amygdala, and medial prefrontal cortex of mutant mice. These changes could be caused by disturbances in neuronal signal transduction; however, it is still unclear whether neuronal activity is reduced in these regions. In this study, we performed in vivo manganese-enhanced magnetic resonance imaging (MEMRI) to assess the regional cellular activity in the brains of αCaMKII HKO mice. The signal intensity of MEMRI 24 h after systemic MnCl2 administration reflects functional increases of Mn(2+) influx into neurons and glia via transport mechanisms, such as voltage-gated and/or ligand-gated Ca(2+) channels. αCaMKII HKO mice demonstrated a low signal intensity of MEMRI in the dentate gyrus (DG), in which almost all neurons were at immature status at the molecular, morphological, and electrophysiological levels. In contrast, analysis of the signal intensity in these mutant mice revealed increased activity in the CA1 area of the hippocampus, a region crucial for cognitive function. The signal intensity was also increased in the bed nucleus of the stria terminalis (BNST), which is involved in anxiety. These changes in the mutant mice may be responsible for the observed dysregulated behaviors, such as cognitive deficit and abnormal anxiety-like behavior, which are similar to symptoms seen in human psychiatric disorders.

Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice.

BACKGROUND: The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders, but cellular mechanisms underlying the antidepressant effect of FLX remain largely unknown. The generally accepted effect of chronic FLX treatment is increased adult neurogenesis in the hippocampal dentate gyrus. It was recently demonstrated that FLX treatments can reverse the established neuronal maturation of granule cells in the hippocampal dentate gyrus and of gamma-aminobutyric acidergic (GABAergic) interneurons in the basolateral amygdala. However, it is not clear whether this dematuration effect of FLX occurs in other brain regions. Thus, in this study, we used immunohistological analysis to assess the effect of FLX treatment on GABAergic interneurons in the medial frontal cortex (mFC) and reticular thalamic nucleus (RTN). RESULTS: Immunofluorescence analysis for perineuronal nets (PNNs), which is a marker of neuronal maturation, and for parvalbumin, calretinin, and somatostatin, which are markers for specific GABAergic interneuron type, showed lower number of parvalbumin-positive (+) cells and PNN+/parvalbumin+ cells in the mFC of FLX-treated mice compared to vehicle-treated mice. However, FLX treatment had no effect on the number of cells expressing calretinin and somatostatin in the mFC. In the RTN, the number of PNN+ cells and parvalbumin+ cells was unaltered by FLX treatments. Furthermore, the number of total GABA+ cells and apoptotic cells in the mFC was similar between vehicle- and FLX-treated mice, suggesting that FLX treatment did not induce cell death in this region. Rather, our findings suggest that the decreased number of parvalbumin+ cells in the mFC was due to a decreased expression of parvalbumin proteins in the interneurons. CONCLUSIONS: This study indicates that FLX decreases the levels of parvalbumin, a mature marker of fast-spiking interneurons, and PNNs in parvalbumin+ interneurons in the mFC, suggesting that FLX treatment induces a dematuration of this type of neurons. Induction of a juvenile-like state in fast-spiking inhibitory interneurons in these regions might be involved in the therapeutic mechanism of this antidepressant drug and/or some of its adverse effects.