Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO ...mouse displays phenotypes similar to symptoms in the human condition—including hyperactivity, repetitive behaviors, and seizures—as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor—which we call FRAX486—also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the
FMR1 gene that encodes ...the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated
Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
•Enrichment (EE) ameliorates impaired spatial learning and enhanced anxiety in depressed rats.•EE restores depression-induced hippocampal atrophy and amygdalar hypertrophy.•Impaired hippocampal ...synaptic plasticity in depression is restored by EE.•EE could be a novel non-pharmacological tool to restore cognitive deficits in depression.
Severe depression compromises structural and functional integrity of the brain and results in impaired learning and memory, maladaptive synaptic plasticity as well as degenerative changes in the hippocampus and amygdala. The precise mechanisms underlying cognitive dysfunctions in depression remain largely unknown. On the other hand, enriched environment (EE) offers beneficial effects on cognitive functions, synaptic plasticity in the hippocampus. However, the effect of EE on endogenous depression associated cognitive dysfunction has not been explored. Accordingly, we have attempted to address this issue by investigating behavioural, structural and synaptic plasticity mechanisms in an animal model of endogenous depression after exposure to enriched environment. Our results demonstrate that depression is associated with impaired spatial learning and enhanced anxiety-like behaviour which is correlated with hypotrophy of the dentate gyrus and amygdalar hypertrophy. We also observed a gross reduction in the hippocampal long-term potentiation (LTP). We report a complete behavioural recovery with reduced indices of anhedonia and behavioural despair, reduced anxiety-like behaviour and improved spatial learning along with a complete restoration of dentate gyrus and amygdalar volumes in depressive rats subjected to EE. Enrichment also facilitated CA3-Schaffer collateral LTP. Our study convincingly proves that depression-induces learning deficits and impairs hippocampal synaptic plasticity. It also highlights the role of environmental stimuli in restoring depression-induced cognitive deficits which might prove vital in outlining more effective strategies to treat major depressive disorders.
Severe and prolonged stress is the main environmental factor that precipitates depression, anxiety and cognitive dysfunctions. On the other hand, exposure to environmental enrichment (EE) has been ...shown to induce progressive plasticity in the brain and improve learning and memory in various neurological and psychiatric disorders. It is not known whether exposure to enriched environment could ameliorate chronic immobilisation stress-induced cognitive deficits and altered molecular markers. Hence, in the present study we aimed to evaluate the effect of enriched environment on chronic immobilisation stress (CIS) associated changes in spatial learning and memory, behavioural measures of anxiety, depression and molecular markers as well as structural alterations. Male Wistar rats were subjected to chronic immobilisation stress for 2h/day/10days followed by 2weeks of exposure to EE. CIS resulted in weight loss, anhedonia, increased immobility, spatial learning and memory impairment, enhanced anxiety, and reduced expression of BDNF, VEGF, GFAP and glucocorticoid receptors (GR) in discrete brain regions. Interestingly, stressed rats exposed to enrichment ameliorated behavioural depression, spatial learning and memory impairment and reduced anxiety behaviour. In addition, EE restored BDNF, VEGF, GFAP and GR expression and normalized hypotrophy of dentate gyrus and hippocampus in CIS rats. In contrast, EE did not restore hypertrophy of the amygdalar complex. Thus, EE ameliorates stress-induced cognitive deficits by modulating the neurotrophic factors, astrocytes and glucocorticoid receptors in the hippocampus, frontal cortex and amygdala.
•Enriched enrichment (EE) exhibited antidepressant activity in CIS model of depression.•EE ameliorates anxiety, spatial learning and memory impairments.•EE restored hippocampal hypotrophy not amygdala hypertrophy.•Enrichment up-regulates the expression of BDNF, VEGF, GFAP and GR.•Neuroprotective effect of EE is through modulation of BDNF, VEGF, GFAP and GR signalling.
Objective: Several studies report that chronic stress results in impaired spatial learning and working memory and enhanced anxiety-like behavior. However, not many studies have looked into the ...possible ways of reversing stress-induced deficits. Celastrus paniculatus (CP), a traditional ayurvedic herbal medicine, was used to treat cognitive deficits in mentally retarded children. CP oil has been reported to have neuroprotective and antioxidant activities. However, the effects of CP oil on chronic stress-induced cognitive deficits are unclear. In the present study, we intended to analyze the neuroprotective effects of CP oil on stress-associated cognitive dysfunctions.
Materials and Methods: Chronic stress was induced by subjecting rats to restrainers for 6 h a day for 21 days. CP oil (400, 600 mg/kg) or vehicle was administered intraperitoneally (i.p.) after stress protocol once a day over the next 14 days. Groups used in the present study: normal control, stress, stress + vehicle, stress + CP oil at 2 different doses (400 and 600 mg/kg, i.p.). After the drug treatment, open field and elevated plus maze (EPM) were used to analyze anxiety-like behavior, and partially baited radial arm maze (RAM) and T-maze were used to evaluate spatial learning and memory capabilities. Analysis has been done using two-way ANOVA followed by Bonferroni's post hoc test and one-way ANOVA followed by Tukey's post hoc test.
Results: Stressed rats showed enhanced anxiety-like behavior in EPM (P < 0.001) and impaired performance in RAM (P < 0.001) and T-maze tasks (P < 0.001) compared to normal animals. In contrast, CP oil treatment to these rats improved their performance in both RAM (P < 0.001) and T-maze (P < 0.001). In addition, CP oil significantly reduced stress-induced anxiety behavior (P < 0.001).
Conclusion: Chronic treatment with CP oil is to improve cognitive abilities in chronically stressed rats. The current study provides a novel perspective on beneficial effect of herbal therapy on stress-induced cognitive dysfunctions.
Finasteride, a 5α-Reductase inhibitor, is used to treat male pattern baldness and benign prostatic hyperplasia. Several clinical studies show that chronic finasteride treatment induces persistent ...depression, suicidal thoughts and cognitive impairment and these symptoms are persistent even after its withdrawal. Previous results from our lab showed that repeated administration of finasteride for six days induces depression-like behavior. However, whether short-term finasteride administration induces anxiety-like behavior and memory impairment and alters synaptic plasticity are not known, which formed the basis of this study. Finasteride was administered to 2–2.5 months old male Wistar rats for six days and subjected to behavioral evaluation, biochemical estimation and synaptic plasticity assessment. Anxiety-like behavior was evaluated in the elevated plus maze (EPM), open field test (OFT), light/dark test (LDT), and novelty suppressed feeding test (NSFT), and learning and memory using novel object recognition test (NORT) and novel object location test (NOLT) and depression-like behavior in the sucrose preference test (SPT). Synaptic plasticity in the hippocampal Schaffer collateral-CA1 was evaluated using slice field potential recordings. Plasma corticosterone levels were estimated using ELISA. Finasteride administration induced anxiety-like behavior in the EPM, OFT, LDT and NSFT, and depression-like behavior in the SPT. Further, finasteride induced hippocampal dependent spatial learning and memory impairment in the NOLT. In addition, finasteride decreased basal synaptic plasticity and long-term potentiation (LTP) in the hippocampus. A trend of increased plasma corticosterone levels was observed following repeated finasteride administration. These results indicate the potential role of corticosterone and synaptic plasticity in finasteride-induced effects and further studies will pave way for the development of novel neurosteroid-based therapeutics in neuropsychiatric diseases.
Rationale
The neural basis of depression-associated cognitive impairment remains poorly understood, and the effect of antidepressants on learning and synaptic plasticity in animal models of ...depression is unknown. In our previous study, learning was impaired in the neonatal clomipramine model of endogenous depression. However, it is not known whether the cognitive impairment in this model responds to antidepressant treatment, and the electrophysiological and neurochemical bases remain to be determined.
Objectives
To address this, we assessed the effects of escitalopram treatment on spatial learning and memory in the partially baited radial arm maze (RAM) task and long-term potentiation (LTP) in the Schaffer collateral-CA1 synapses in neonatal clomipramine-exposed rats. Also, alterations in the levels of biogenic amines and acetylcholinesterase (AChE) activity were estimated.
Results
Fourteen days of escitalopram treatment restored the mobility and preference to sucrose water in the forced swim and sucrose consumption tests, respectively. The learning impairment in the RAM was reversed by escitalopram treatment. Interestingly, CA1-LTP was decreased in the neonatal clomipramine-exposed rats, which was restored by escitalopram treatment. Monoamine levels and AChE activity were decreased in several brain regions, which were restored by chronic escitalopram treatment.
Conclusions
Thus, we demonstrate that hippocampal LTP is decreased in this animal model of depression, possibly explaining the learning deficits. Further, the reversal of learning and electrophysiological impairments by escitalopram reveals the important therapeutic effects of escitalopram that could benefit patients suffering from depression.
•Finasteride does not show acute effects either immediately or 24h after administration in both the FST and splash test.•Three doses of finasteride increased the latency to groom and decreased the ...total grooming duration in the splash test.•Six doses of finasteride also induced a depression-like phenotype in the FST and splash test.
The enzyme 5α-Reductase (5α-R) catalyzes the formation of dihydrotestosterone, which is involved in male pattern hair loss and benign prostatic hyperplasia. Finasteride inhibits 5α-R and is used to treat both these conditions. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts, and cognitive impairment. The neural mechanisms underlying these effects of finasteride are not known and it is imperative that an animal model that mimics the clinical neuropsychiatric effects of finasteride is developed. Accordingly, we evaluated the behavioral effects of acute and repeated finasteride administration. Two months old male Wistar rats were administered with either vehicle (hydroxypropyl-β-cyclodextrin) or different doses of finasteride, subcutaneously, either acutely (30 min or 2 h) or for 1, 3, and 6 days (one dose per day). Behavioral despair and motivational behavior were evaluated in the forced swim test (FST) and splash test, respectively. FST and splash test were video-recorded and analyzed offline. Finasteride did not show any effects in the acute, one day or three days studies in the FST. However, repeated finasteride administration for 6 days significantly increased the immobility time. In the splash test, finasteride (100 mg/kg) administration increased the latency to groom and decreased the grooming duration implying lack of motivation in the three-day study. In the six-day study, latency to groom was significantly increased by the 100 mg/Kg dose. Further, a significant dose dependent decrease in the grooming duration was observed. In summary, our results indicate that repeated finasteride administration induces depression-like behavior in rats. This study provides the evidence that an animal model of finasteride-induced depression is feasible to investigate the cellular and molecular mechanisms, and the pharmacology underlying the neuropsychiatric effects of finasteride. Further, these results provide insights into the potential involvement of neurosteroids in depression and will lead to the development of novel therapeutics for its treatment.
Rationale
Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) ...axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that
N
-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown.
Objectives
Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex.
Results
We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX).
Conclusions
We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
The hippocampus and the amygdala are essential components of the neural circuitry mediating stress responses. The hippocampus, which provides negative feedback regulation of the stress response, is ...particularly vulnerable to degenerative changes caused by chronic stress. Unlike the hippocampus, relatively little is known about how stress affects the amygdala and the nature of its role in the stress response. Hence, we examined the effects of two different models of chronic stress on hippocampal and amygdaloid neuronal morphology in rats. In agreement with previous reports, chronic immobilization stress (CIS) induced dendritic atrophy and debranching in CA3 pyramidal neurons of the hippocampus. In striking contrast, pyramidal and stellate neurons in the basolateral complex of the amygdala exhibited enhanced dendritic arborization in response to the same CIS. Chronic unpredictable stress (CUS), however, had little effect on CA3 pyramidal neurons and induced atrophy only in BLA bipolar neurons. These results indicate that chronic stress can cause contrasting patterns of dendritic remodeling in neurons of the amygdala and hippocampus. Moreover, CIS, but not CUS, reduced open-arm activity in the elevated plus-maze. These findings raise the possibility that certain forms of chronic stress, by affecting specific neuronal elements in the amygdala, may lead to behavioral manifestations of enhanced emotionality. Thus, stress-induced structural plasticity in amygdala neurons may provide a candidate cellular substrate for affective disorders triggered by chronic stress.
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