Genetic Rat Model Of Depression Research Articles

5HT1AR-FGFR1 Heteroreceptor Complexes Differently Modulate GIRK Currents in the Dorsal Hippocampus and the Dorsal Raphe Serotonin Nucleus of Control Rats and of a Genetic Rat Model of Depression.

The midbrain raphe serotonin (5HT) neurons provide the main ascending serotonergic projection to the forebrain, including hippocampus, which has a role in the pathophysiology of depressive disorder. Serotonin 5HT1A receptor (R) activation at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons leads to a decrease in neuronal firing by activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels. In this raphe-hippocampal serotonin neuron system, the existence of 5HT1AR-FGFR1 heteroreceptor complexes has been proven, but the functional receptor-receptor interactions in the heterocomplexes have only been investigated in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the current study, considering the impact of the receptor interplay in developing new antidepressant drugs, the effects of 5HT1AR-FGFR1 complex activation were investigated in hippocampal pyramidal neurons and in midbrain dorsal raphe serotonergic neurons of SD rats and of a genetic rat model of depression (the Flinders Sensitive Line (FSL) rats of SD origin) using an electrophysiological approach. The results showed that in the raphe-hippocampal 5HT system of SD rats, 5HT1AR-FGFR1 heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels through the allosteric inhibitory interplay produced by the activation of the FGFR1 protomer, leading to increased neuronal firing. On the contrary, in FSL rats, FGFR1 agonist-induced inhibitory allosteric action at the 5HT1AR protomer was not able to induce this effect on GIRK channels, except in CA2 neurons where we demonstrated that the functional receptor-receptor interaction is needed for producing the effect on GIRK. In keeping with this evidence, hippocampal plasticity, evaluated as long-term potentiation induction ability in the CA1 field, was impaired by 5HT1AR activation both in SD and in FSL rats, which did not develop after combined 5HT1AR-FGFR1 heterocomplex activation in SD rats. It is therefore proposed that in the genetic FSL model of depression, there is a significant reduction in the allosteric inhibition exerted by the FGFR1 protomer on the 5HT1A protomer-mediated opening of the GIRK channels in the 5HT1AR-FGFR1 heterocomplex located in the raphe-hippocampal serotonin system. This may result in an enhanced inhibition of the dorsal raphe 5HT nerve cell and glutamatergic hippocampal CA1 pyramidal nerve cell firing, which we propose may have a role in depression.

Sex and Estrous Cycle Are Not Mediators of S-Ketamine's Rapid-Antidepressant Behavioral Effects in a Genetic Rat Model of Depression.

Recent preclinical and clinical studies have shed light on the possible impact of sex and estrous/menstrual cycle on ketamine's antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioral responses to a subanesthetic dose of S-ketamine in males vs females and in different estrous phases in free-cycling females in a well-powered translational approach. We evaluated the behavioral sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders Sensitive Line rats (FSLs) and their counterpart Flinders Resistant Line rats (FRLs) subjected to the open field and forced swim tests. Female rats were disaggregated into different estrous phases, and the behavioral outcomes were compared. Acute administration of S-ketamine had robust antidepressant-like effects in FSLs. Within our study power, we could not detect sex- or estrous cycle-specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different estrous cycles did not behaviorally affect S-ketamine's rapid-acting antidepressant mode of action. No sex-related or estrous cycle-related impact on behavioral despair was observed even among FRLs and saline-treated FSLs. We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioral antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive-like and anxiety-like behaviors.

The monoamine stabilizer OSU6162 has anxiolytic-like properties and reduces voluntary alcohol intake in a genetic rat model of depression

Alcohol use disorders (AUD) often co-occur with anxiety and depressive disorders, and anxiety often drives relapse during alcohol abstinence. Optimal AUD pharmacotherapies may thus need to target both excessive alcohol intake and elevated anxiety. (−)-OSU6162 (OSU) is a monoamine stabilizer that attenuates alcohol-mediated behaviors in both preclinical and clinical settings. However, OSU’s effect on anxiety-like behavior following long-term drinking remains unknown. To this end, we utilized a genetic rat model that exhibits increased anxiety- and depression-like behaviors (Flinders Sensitive Line; FSL) and their controls (Flinders Resistant Line; FRL). Using the novelty suppressed feeding (NSF) test, we evaluated anxiety-like behaviors (1) at baseline, (2) following long-term voluntary drinking and after 24 h of alcohol deprivation, and (3) following OSU administration in the same animals. At baseline, FSL animals displayed significantly elevated anxiety-like characteristics compared to FRL. Compared to alcohol-naïve animals, long-term drinking significantly reduced anxiety-like behaviors in FSL, without any significant effects in FRL animals. Compared to vehicle, OSU administration significantly reduced anxiety-like behaviors in alcohol-naïve FSL and long-term drinking FRL animals. While there was no significant difference in alcohol intake between FSL and FRL, OSU attenuated alcohol intake in both strains. Conclusively, in addition to the compound’s previously identified ability to suppress alcohol-mediated behaviors, OSU may also possess anxiolytic properties, warranting further clinical evaluation in both AUD and anxiety disorder settings.

Hypothalamic Gene Expression and Postpartum Behavior in a Genetic Rat Model of Depression.

Postpartum depression is a complex illness that often occurs in genetically predisposed individuals. Closely related inbred rat strains are a great resource to identify novel causative genes and mechanisms underlying complex traits such as postpartum behavior. We report differences in these behaviors between the inbred depression model, Wistar Kyoto (WKY) More Immobile (WMI), and the isogenic control Wistar Kyoto Less Immobile (WLI) dams. WMI dams showed significantly lower litter survival rate and frequency of arched back and blanket nursing, but increased pup-directed licking, grooming, and retrieval during postpartum days (PPD) 1–10, compared to control WLIs. This increased pup-directed behavior and the frequency of self-directed behaviors segregated during selective breeding of the progenitor strain of WKY, which is also a depression model. These behaviors are manifested in the WMIs in contrast to those of WLIs. Furthermore, habitual differences in the self-directed behavior between light and dark cycles present in WLIs were missing in WMI dams. Hypothalamic transcript levels of the circadian rhythm-related gene Lysine Demethylase 5A (Kdm5a), period 2 (Per2), and the maternal behavior-related oxytocin receptor (Oxtr), vasopressin (Avp), and vasopressin receptor 1a (Avpr1a) were significantly greater in the post-weaning WMI dams at PPD 24 compared to those of WLIs, and also to those of WMI dams whose litter died before PPD 5. Expression correlation amongst genes differed in WLI and WMI dams and between the two time-points postpartum, suggesting genetic and litter-survival differences between these strains affect transcript levels. These data demonstrate that the genetically close, but behaviorally disparate WMI and WLI strains would be suitable for investigating the underlying genetic basis of postpartum behavior.

Non-dopaminergic Alterations in Depression-Like FSL Rats in Experimental Parkinsonism and L-DOPA Responses.

Depression is a common comorbid condition in Parkinson’s disease (PD). Patients with depression have a two-fold increased risk to develop PD. Further, depression symptoms often precede motor symptoms in PD and are frequent at all stages of the disease. However, the influence of a depressive state on the responses to antiparkinson treatments is largely unknown. In this study, the genetically inbred depression-like flinders sensitive line (FSL) rats and control flinders resistant line (FRL) rats were studied in models of experimental parkinsonism. FSL rats showed a potentiated tremorgenic response to tacrine, a cholinesterase inhibitor used experimentally to induce 6 Hz resting tremor reminiscent of parkinsonian tremor. We also studied rats lesioned with 6-OHDA to induce hemiparkinsonism. No baseline differences in dopaminergic response to acute apomorphine or L-DOPA was found. However, following chronic treatment with L-DOPA, FRL rats developed sensitization of turning and abnormal involuntary movements (AIMs); these effects were counteracted by the anti-dyskinetic 5-HT1A agonist/D2 partial agonist sarizotan. In contrast, FSL rats did not develop sensitization of turning and only minor AIMs in response to L-DOPA treatment. The roles of several non-dopamine systems underlying this discrepancy were studied. Unexpectedly, no differences of opioid neuropeptides or serotonin markers were found between FRL and FSL rats. The marked behavioral difference between the FRL and FSL rats was paralleled with the striatal expression of the established marker, c-fos, but also the GABAergic transporter (vGAT), and a hitherto unknown marker, tamalin, that is known to regulate mGluR5 receptor function and postsynaptic organization. This study demonstrates that behavioral and transcriptional responses of non-dopaminergic systems to experimental parkinsonism and L-DOPA are modified in a genetic rat model of depression.

Cortical and striatal serotonin transporter binding in a genetic rat model of depression and in response to electroconvulsive stimuli

Depression is a debilitating mental illness and two thirds of patients respond insufficiently to conventional antidepressants. Electroconvulsive therapy (ECT) remains the most effective treatment to alleviate drug-refractory depression, however the neurobiological mechanisms are mostly unknown. The serotonergic system plays an important role in depression and alterations in the serotonin transporter (SERT) are seen both in depression and response to antidepressant pharmacotherapies. The first aim of this study was to investigate SERT density in a genetic rat model of depression, Flinders Sensitive Line (FSL), compared to control Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats. The second aim was to investigate SERT density in response to electroconvulsive stimuli (ECS), an animal model of ECT. Female rats of each strain were treated with ECS or sham (ear-clip placement with no current) for 10 days before brains were removed, frozen and cut into 20 µm thick sections. SERT density was measured in striatal and cortical regions by quantitative in vitro autoradiography using the SERT-radioligand, [3H]-DASB. Higher SERT density was observed in FSL rats compared to SD rats by 36–48% in motor cortex and striatum under sham conditions. In response to ECS, SD rats displayed a significant effect of treatment, whereas no changes were observed in FRL and FSL rats. Increased SERT binding in FSL rats compared to SD supports a dysfunction of the serotonergic system in depression. The increased SERT density after ECS, seen in SD rats but not FSL rats, suggests a different mechanism of action between depressive-like rats and controls.

Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression

Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats. We analyzed each region for the eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels by liquid chromatography/multiple reaction monitoring (LC/MRM), mRNA and protein levels of the cannabinoid type 1 receptor (CB1R), fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) by real time qPCR and Western blotting. Content of 2-AG was lower in the left side of the hippocampus and prefrontal cortex in FSL rats compared to FRL rats. Inversely, levels of AEA were higher in right hippocampus than in left hippocampus. In plasma, AEA levels were increased and 2-AG decreased. Cannabinoid receptor 1 (Cnr1), Faah and Magl mRNA levels were prominently decreased in right prefrontal cortex of FSL rats as compared to FRL rats. Protein expression of CB1R and FAAH were decreased in left hippocampus. In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour. Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions. Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.

Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression

Aging and major depressive disorder are risk factors for dementia, including Alzheimer’s Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression-like behavior in this model.

Prepubertal Ovariectomy Exaggerates Adult Affective Behaviors and Alters the Hippocampal Transcriptome in a Genetic Rat Model of Depression.

Major depressive disorder (MDD) is a debilitating illness that affects twice as many women than men postpuberty. This female bias is thought to be caused by greater heritability of MDD in women and increased vulnerability induced by female sex hormones. We tested this hypothesis by removing the ovaries from prepubertal Wistar Kyoto (WKY) more immobile (WMI) females, a genetic animal model of depression, and its genetically close control, the WKY less immobile (WLI). In adulthood, prepubertally ovariectomized (PrePubOVX) animals and their Sham-operated controls were tested for depression- and anxiety-like behaviors, using the routinely employed forced swim and open field tests, respectively, and RNA-sequencing was performed on their hippocampal RNA. Our results confirmed that the behavioral and hippocampal expression changes that occur after prepubertal ovariectomy are the consequences of an interaction between genetic predisposition to depressive behavior and ovarian hormone-regulated processes. Lack of ovarian hormones during and after puberty in the WLIs led to increased depression-like behavior. In WMIs, both depression- and anxiety-like behaviors worsened by prepubertal ovariectomy. The unbiased exploration of the hippocampal transcriptome identified sets of differentially expressed genes (DEGs) between the strains and treatment groups. The relatively small number of hippocampal DEGs resulting from the genetic differences between the strains confirmed the genetic relatedness of these strains. Nevertheless, the differences in DEGs between the strains in response to prepubertal ovariectomy identified different molecular processes, including the importance of glucocorticoid receptor-mediated mechanisms, that may be causative of the increased depression-like behavior in the presence or absence of genetic predisposition. This study contributes to the understanding of hormonal maturation-induced changes in affective behaviors and the hippocampal transcriptome as it relates to genetic predisposition to depression.

S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression.

Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role.Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine.Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1–6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity.Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine’s acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction.Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine’s antidepressant-like potentials in this model.

Disturbances in the FGFR1-5-HT1A Heteroreceptor Complexes in the Raphe-Hippocampal 5-HT System Develop in a Genetic Rat Model of Depression.

The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.

Ketamine and aminoguanidine differentially affect Bdnf and Mtor gene expression in the prefrontal cortex of adult male rats

The rapid and sustained antidepressant properties of ketamine provide evidence of the importance of the glutamatergic system in the neurobiology of depression. The antidepressant-like effects of ketamine are dependent on brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in limbic brain areas. The nitrergic system is closely related to the glutamatergic system and generates antidepressant-like effects when blocked. The aim of this study was to investigate whether the behavioural effects induced by the inhibition of nitric oxide (NO) synthesis by aminoguanidine or N-methyl-D-aspartate (NMDA) receptor blockade by ketamine would affect the gene expression of Bdnf and Mtor in the ventromedial prefrontal cortex in rats. The effects of ketamine or aminoguanidine were investigated in Sprague-Dawley (SD) rats, the Flinders Sensitive Line (FSL), a genetic rat model of depression, and their controls, the Flinders Resistant Line (FRL) rats. In the studies, the three protocols evaluated to which the animals/rats were exposed were: (1) pre-test and test sessions of forced swim test (FST), (2) pre-test session of FST alone, or (3) not exposed to the FST. Ketamine and aminoguanidine both induce antidepressant-like effects in SD and FSL rats. Quantitative real-time polymerase chain reaction analyses in SD rats demonstrated that none of the treatments can change the Bdnf or Mtor gene expression, but in FSL rats the treatment with ketamine increased only Bdnf gene expression. The data obtained strengthens the role of NMDA antagonists and NO inhibitors as potential antidepressant drugs, albeit with different effects on Bdnf gene expression.

Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior.

The metabolism of tryptophan through kynurenine and serotonin pathways is linked to depression. Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine, and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry (LC-MS/MS), in Flinders Sensitive Line rats, a genetic rat model of depression, and its controls: Flinders Sensitive Line and Sprague-Dawley rats. Protein levels of kynurenine pathway enzymes were measured in the brains and livers of these rat strains. Furthermore, effects of vortioxetine on tryptophan metabolites were assessed in the cortical regions of lupus mice (MRL/MpJ-FasIpr ), a murine model of increased depression-like behavior associated with inflammation. Sustained vortioxetine or fluoxetine (at doses aimed to fully occupy serotonin transporter via food or drinking water for at least 14days) reduced levels of the excitotoxin quinolinic acid (QUIN) in various brain regions in all rats. Furthermore, chronic vortioxetine reduced levels of QUIN in MRL/MpJ-FasIpr mice. Acute i.p. administration of fluoxetine (10mg/kg) or vortioxetine (10mg/kg) led to reduced brain 5-hydroxyindoleacetic acid in Sprague-Dawley rats (2, 4, 6, and 8h) and a similar trend was evident in Flinders Sensitive Line and Flinders Sensitive Line rats after 4h. In contrast, single or repeated administration of ketamine (15mg/kg i.p.) did not induce significant changes in metabolite levels. In conclusion, sustained vortioxetine and fluoxetine administration decreased QUIN independent of species, while ketamine was ineffective. These results support the hypothesis that modulating tryptophan metabolism may be part of the mechanism of action for some antidepressants.

Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression.

Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real-time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2×105; 10 μl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus.

S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression.

Background:The neurovascular plasticity of hippocampus is an important theory underlying major depression. Ketamine as a novel glutamatergic antidepressant drug can induce a rapid antidepressant effect within hours. In a mechanistic proof of this concept, we examined whether ketamine leads to an increase in synaptogenesis and vascularization within 24 hours after a single injection in a genetic rat model of depression.Methods:Flinders Sensitive Line and Flinders Resistant Line rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline. One day later, their behavior was evaluated by a modified forced swim test. Microvessel length was evaluated with global spatial sampling and optical microscopy, whereas the number of asymmetric synapses was quantified through serial section electron microscopy by using physical disector method in the CA1.stratum radiatum area of hippocampus.Results:The immobility time in the forced swim test among Flinders Sensitive Line rats with ketamine treatment was significantly lower compared with Flinders Sensitive Line rats without treatment. The number of nonperforated and perforated synapses was significantly higher in the Flinders Sensitive Line-ketamine vs the Flinders Sensitive Line-vehicle group; however, ketamine did not induce a significant increase in the number of shaft synapses. Additionally, total length of microvessels was significantly increased 1 day after ketamine treatment in Flinders Sensitive Line rats in the hippocampal subregions, including the CA1.stratum radiatum.Conclusion:Our findings indicate that hippocampal vascularization and synaptogenesis is co-regulated rapidly after ketamine, and microvascular elongation may be a supportive factor for synaptic plasticity and neuronal activity. These findings go hand-in-hand with the behavioral observations, where ketamine acts as a potent antidepressant.

Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression.

Stress, such as social isolation, is a well-known risk factor for depression, most probably in combination with predisposing genetic factors. Physical exercise on the other hand, is depicted as a wonder-treatment that makes you healthier, happier and live longer. However, the published results on the effects of exercise are ambiguous, especially when it comes to neuropsychiatric disorders. Here we combine a paradigm of social isolation with a genetic rat model of depression, the Flinders Sensitive Line (FSL), already known to have glutamatergic synaptic alterations. Compared to group-housed FSL rats, we found that social isolation further affects synaptic plasticity and increases basal synaptic transmission in hippocampal CA1 pyramidal neurons. These functional synaptic alterations co-exist with changes in hippocampal protein expression levels: social isolation in FSL rats reduce expression of the glial glutamate transporter GLT-1, and increase expression of the GluA2 AMPA-receptor subunit. We further show that physical exercise in form of voluntary running prevents the stress-induced synaptic effects but do not restore the endogenous mechanisms of depression already present in the FSL rat.

Elevation of Il6 is associated with disturbed let-7 biogenesis in a genetic model of depression.

Elevation of the proinflammatory cytokine IL-6 has been implicated in depression; however, the mechanisms remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression post-transcriptionally. The lethal-7 (let-7) miRNA family was suggested to be involved in the inflammation process and IL-6 was shown to be one of its targets. In the present study, we report elevation of Il6 in the prefrontal cortex (PFC) of a genetic rat model of depression, the Flinders Sensitive Line (FSL) compared to the control Flinders Resistant Line. This elevation was associated with an overexpression of LIN28B and downregulation of let-7 miRNAs, the former an RNA-binding protein that selectively represses let-7 synthesis. Also DROSHA, a key enzyme in miRNA biogenesis was downregulated in FSL. Running was previously shown to have an antidepressant-like effect in the FSL rat. We found that running reduced Il6 levels and selectively increased let-7i and miR-98 expression in the PFC of FSL, although there were no differences in LIN28B and DROSHA expression. Pri-let-7i was upregulated in the running FSL group, which associated with increased histone H4 acetylation. In conclusion, the disturbance of let-7 family biogenesis may underlie increased proinflammatory markers in the depressed FSL rats while physical activity could reduce their expression, possibly through regulating primary miRNA expression via epigenetic mechanisms.

Antidepressant efficacy of high and low frequency transcranial magnetic stimulation in the FSL/FRL genetic rat model of depression

Repetitive Magnetic Stimulation (rTMS) has appeared to be a potential non-invasive antidepressant method, which implies non-convulsive focal stimulation of the brain through a time varying magnetic field. The antidepressant potential of rTMS has been supported by animal studies showing a number of interesting similarities between magnetic stimulation and electroconvulsive stimulation (ECS). Despite these positive results, this method still contains many unknown issues. Importantly, there are fundamental uncertainties concerning the optimal combination of stimulus parameters (frequency, intensity, duration, and number of pulses) to obtain an antidepressant effect. Therefore, the present study aimed to qualify the choice of rTMS stimulus frequency in a well-validated genetic animal model of depression, the FSL/FRL rats. We compared the antidepressant effect of low frequency, high frequency rTMS and ECS to sham treatment in FRL and FSL rats using 6 parallel groups. We used the Forced Swim Test and the Open Field Test to screen the depression-like state in rats. We found that both the high frequency and the low frequency rTMS resulted in a significant antidepressant effect. However, this effect was inferior to the effect of ECS. The low frequency and high frequency groups, which received the same total impulse load and stimulus intensity, did not differ with respect to antidepressant efficacy in this study. In conclusion, this study provides robust evidence that both rTMS interventions are efficacious, although not as efficient as ECS.

Neurovascular plasticity of the hippocampus one week after a single dose of ketamine in genetic rat model of depression.

Glutamatergic system and the structural plasticity hypothesis are principal components for rapid and sustained antidepressant effects of novel antidepressant therapeutics. This study represents the first investigation of the structural plasticity of the hippocampus as one of the main contributed mechanisms to the sustained anti-depressive effect of ketamine. Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline 7 days before perfusion-fixed. The optical fractionator method was used to estimate the total number of neurons in the granular cell layer. Microvessel length in the molecular layer of DG was evaluated with global spatial sampling method. By use of the physical disector method, the number of synapses was estimated. The volume of the hippocampus was larger in the FRL-vehicle rats compared with FSL-vehicle group and in FSL-ketamine versus FSL-vehicle rats (P < 0.05). The number of non-perforated synapses was significantly higher in the FSL-ketamine versus FSL-vehicle group, (P = 0.01). A significant effect of ketamine on enhancement of the number of neurons in DG in FSL rats was observed (P = 0.01). The total length of the microvessels 1 week after ketamine treatment in the FSL rats significantly increased (P < 0.05). Our results indicate that neurovascular changes of hippocampus could be one of the possible mechanisms underlying the sustained antidepressant effect of ketamine by reversing alteration of the number of the excitatory synapses, neuronal number and length of the microvessels in the hippocampus. © 2016 Wiley Periodicals, Inc.