Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10 mg/kg and ketamine at the dose of 5 mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20 mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.     

Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala.     

Effects of olanzapine, fluoxetine and olanzapine/fluoxetine on creatine kinase activity in rat brain

Recently, a fixed combination of the atypical antipsychotic olanzapine and the serotonin selective reuptake inhibitor (SSRI) fluoxetine has been approved in the US for the treatment of bipolar I depression. In this work, we evaluated the effect of acute and chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on creatine kinase (CK) activity in the brain of rats. For acute treatment, adult male Wistar rats received one single injection of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25 mg/kg). For chronic treatment, adult male Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25 mg/kg) for 28 days. In the present study we observed that acute administration of OLZ inhibited CK activity in cerebellum and prefrontal cortex. The acute administration of FLX inhibited creatine kinase in cerebellum, prefrontal cortex, hippocampus, striatum and cerebral cortex. In the chronic treatment, when the animals were killed 2 h after the last injection a decrease in creatine kinase activity after FLX administration, alone or in combination with OLZ, in cerebellum, prefrontal cortex, hippocampus, striatum and cerebral cortex of rats occurred. However, when the animals were killed 24 h after the last injection, we found no alterations in the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of creatine kinase activity by these drugs may be associated to the occurrence of some side effects of OLZ and FLX.     

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-d-aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II–III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.     

Acute renal failure potentiates brain energy dysfunction elicited by methylmalonic acid

The influence of acute renal failure induced by gentamicin administration on the effects of MMA on mitochondrial respiratory chain complexes, citrate synthase, succinate dehydrogenase and creatine kinase activities in cerebral cortex and kidney of young rats were investigated. Animals received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 μmol/g) or saline (11 h interval between injections) and 60 min after the last injection the animals were killed. Acute MMA administration decreased creatine kinase activity in both tissues and increased complexes I–III activity in cerebral cortex. Creatine kinase activity was also inhibited by gentamicin administration. Simultaneous administration of MMA and gentamicin increased the activities of citrate synthase in cerebral cortex and kidney and complexes II–III in cerebral cortex. The other enzyme activities in cerebral cortex and kidney of animals receiving MMA plus gentamicin did not significantly differ from those observed in animals receiving only MMA. Our present data is line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on the Krebs cycle and respiratory chain in brain and peripheral tissues.     

Antidepressant-Like Action of Single Facial Injection of Botulinum Neurotoxin A is Associated with Augmented 5-HT Levels and BDNF/ERK/CREB Pathways in Mouse Brain

The present study was designed to examine the therapeutic effects of Botulinum neurotoxin A(BoNT/A)on depression-like behaviors in mice and to explore the potential mechanisms.These results revealed that a single facial injection of BoNT/A induced a rapid and prolonged improvement of depression-like behaviors in naive and space-restriction-stressed(SRS)mice,reflected by a decreased duration of immobility in behavioral despair tests.BoNT/A significantly increased the 5-hydroxytryptamine(5-HT)levels in several brain regions,including the hippocampus and hypothalamus,in SRS mice.BoNT/A increased the expression of the N-methyl-Daspartate receptor subunits NR1 and NR2 B in the hippocampus,which were significantly decreased in SRS mice.Furthermore,BoNT/A significantly increased the expression of brain-derived neurotrophic factor(BDNF)in the hippocampus,hypothalamus,prefrontal cortex,and amygdala,which were decreased in SRS mice.Finally,BoNT/A transiently increased the levels of phosphorylated extracellular signal-regulated kinase(p-ERK)and cAMPresponse element binding protein(p-CREB),which were suppressed in the hippocampus of SRS mice.Collectively,these results demonstrated that BoNT/A treatment has antidepressant-like activity in mice,and this is associated with increased 5-HT levels and the activation of BDNF/ERK/CREB pathways in the hippocampus,supporting further investigation of BoNT/A therapy in depression.     

Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats.

BACKGROUND: Estradiol affects neuronal plasticity, mood, and cognition. We examined the effects of the estrous cycle, acute and chronic estradiol treatments on BDNF mRNA expression in the hippocampus and cortex of female rats. The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored. METHODS: BDNF mRNA levels were measured using in situ hybridization at proestrus and estrus, and following acute and chronic estradiol treatment of acutely and chronically ovariectomized (OVX) female rats. Some rats were pretreated with 5-HT2A agonist and antagonist, and another group was subjected to two-hour immobilization stress. RESULTS: BDNF mRNA levels in the dentate gyrus and the medial prefrontal cortex were decreased during estrus, when estradiol levels are highest. Acute estradiol treatment decreased hippocampal BDNF mRNA in acutely OVX rats, but neither acute nor chronic estradiol had effect in chronically OVX rats. Estradiol pretreatment reduced the 5-HT2A receptor-mediated cortical upregulation in BDNF mRNA and did not effect the stress-induced down-regulation of BDNF mRNA in the dentate gyrus. CONCLUSIONS: The duration of the estradiol treatment and the duration of the ovarian hormone deprivation are important factors in the regulation of BDNF synthesis and possibly in the functional outcome of estrogen treatment.     

Amygdala stimulation ameliorates memory impairments and promotes c-Fos activity in fimbria-fornix-lesioned rats

Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.     

Mitochondrial respiratory chain and creatine kinase activities in mdx mouse brain

In this study we investigated energy metabolism in the mdx mouse brain.To this end, prefrontal cortex, cerebellum, hippocampus, striatum, and cortex were analyzed. There was a decrease in Complex I but not in Complex II activity in all structures. There was an increase in Complex III activity in striatum and a decrease in Complex IV activity in prefrontal cortex and striatum. Mitochondrial creatine kinase activity was increased in hippocampus, prefrontal cortex, cortex, and striatum. Our results indicate that there is energy metabolism dysfunction in the mdx mouse brain. Muscle Nerve, 2010     

Adaptation of monoaminergic responses to phencyclidine in nucleus accumbens and prefrontal cortex following repeated treatment with fluoxetine or imipramine

The adaptive neuronal changes that follow chronic administration of antidepressant drugs are thought to underlie clinical improvement in patient populations. Recent evidence suggests that alterations specific to N-methyl-D-aspartate (NMDA) receptors may be a final common pathway to antidepressant action. To investigate this possibility, we sought to establish the effects of chronic fluoxetine or imipramine treatment on the monoamine stimulating effect of the non-competitive NMDA antagonist phencyclidine. Male, Sprague-Dawley rats (n=9/group) were treated with saline (1 ml/kg, i.p.), imipramine (10 mg/kg, i.p.) or fluoxetine (10 mg/kg, i.p.) once daily for 14 consecutive days. After a 7-day drug-free period, animals given an acute challenge of either saline or phencyclidine (5 mg/kg, i.p.). One hour later, animals were killed, brains were removed, and the prefrontal cortex, striatum, and nucleus accumbens were dissected. Samples were assayed for the monoamines and their primary metabolites by HPLC. Repeated treatment with fluoxetine or imipramine did not alter baseline dopamine or serotonin turnover. Acute phencyclidine treatment increased prefrontal cortex and nucleus accumbens dopamine turnover in saline-treated animals (P<0.01); however, the effect in the nucleus accumbens was prevented in animals pretreated with imipramine or fluoxetine. Acute phencyclidine challenge also increased serotonin turnover in prefrontal cortex of saline- or imipramine-pretreated rats (P<0.01), though this effect was attenuated in animals pretreated with fluoxetine. Overall, the data suggest that repeated antidepressant treatment alters monoamine turnover in specific brain regions in response to blockade of NMDA receptors. The data highlight the importance of adaptive responses to NMDA receptors resulting from chronic antidepressant treatment.     

The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels

The reported increase in brain-derived neurotrophic factor (BDNF) mRNA expression after antidepressant treatment is a cornerstone of the BDNF hypothesis of antidepressant action. However, if this increase becomes manifest on the BDNF protein level is unknown. In the present study we performed parallel measurements of BDNF mRNA and protein expression in the frontal cortex and hippocampus of the rat after chronic treatment with electroconvulsive seizures (ECS), lithium, desipramine or escitalopram. ECS increased BDNF mRNA and protein in the hippocampus and BDNF protein in the frontal cortex. Desipramine moderately increased BDNF mRNA expression in the dentate gyrus but did not change BDNF protein in neither region. Escitalopram did not affect BDNF mRNA expression, but decreased BDNF protein in the frontal cortex and the hippocampus. Lithium increased BDNF protein levels in the hippocampus and frontal cortex, but overall decreased BDNF mRNA expression. Thus, here we report a striking non-correspondence between changes in BDNF mRNA and protein expression induced by the antidepressant treatments and lithium. Further, increased expression of BDNF mRNA or protein was not a common action of the treatments. We also investigated if treatment-induced modulations of the tissue contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxy-indoleacetic acid (5-HIAA), were related to changes in BDNF mRNA or protein expression. No correlation was found. However, all treatments increased 5-HT levels in the hippocampus.     

Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus

Harmine is a β-carboline alkaloid that inhibits monoamine reuptake systems. Findings point to an antidepressant effect of the compounds that increases the levels of monoamines after monoamine oxidase inhibition. The present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of harmine and imipramine in rats. To this aim, rats were acutely treated with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavior was assessed in the forced swimming and open-field tests. Afterwards, hippocampal BDNF protein levels were assessed in imipramine- and harmine-treated rats by ELISA-sandwich assay. We observed that harmine at doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time, and increased both climbing and swimming time of rats compared to saline group, without affecting locomotor activity. Acute administration of harmine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. Finally, these findings further support the hypothesis that harmine could be a new pharmacological target for the treatment of mood disorders.     

Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core symptom of depression, was assessed by measuring consumption of a palatable solution. Exposure to CUS reduced intake of a palatable solution and this effect was prevented by chronic antidepressant treatment. Moreover, chronic antidepressant treatment decreased depressive-like behavior in a modified forced swim test in stressed rats. Present evidence suggests a role for brain-derived neurotrophic factor (BDNF) in depression. BDNF mRNA levels in the ventral and dorsal hippocampus were assessed by in situ hybridization. Exposure to CUS was not correlated with a decrease but rather with an increase in BDNF mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity.     

Methylphenidate Treatment Leads to Abnormalities on Krebs Cycle Enzymes in the Brain of Young and Adult Rats

Studies have shown a relationship between energy metabolism and methylphenidate (MPH); however, there are no studies evaluating the effects of MPH in Krebs cycle. So, we investigated if MPH treatment could alter the activity of citrate synthase (CS), malate dehydrogenase (MD), and isocitrate dehydrogenase (ID) in the brain of young and adult Wistar rats. Our results showed that MPH (2 and 10 mg/kg) reduced CS in the striatum and prefrontal cortex (PF), with MPH at all doses in the cerebellum and hippocampus after chronic treatment in young rats. In adult rats the CS was reduced in the cerebellum after acute treatment with MPH at all doses, and after chronic treatment in the PF and cerebellum with MPH (10 mg/kg), and in the hippocampus with MPH (2 and 10 mg/kg). The ID decreased in the hippocampus and striatum with MPH (2 and 10 mg/kg), and in the cortex (10 mg/kg) after acute treatment in young rats. In adult rats acute treatment with MPH (2 and 10 mg/kg) reduced ID in the cerebellum, and with MPH (10 mg/kg) in the cortex; chronic treatment with MPH (10 mg/kg) decreased ID in the PF; with MPH (2 and 10 mg/kg) in the cerebellum, and with MPH at all doses in the hippocampus. The MD did not alter. In conclusion, our results suggest that MPH can alter enzymes of Krebs cycle in brain areas involved with circuits related with attention deficit hyperactivity disorder; however, such effects depend on age of animal and treatment regime.     

Effect of the novel sigma1 receptor ligand and putative atypical antipsychotic E-5842 on BDNF mRNA expression in the rat brain

Changes in the expression of brain-derived neurotrophic factor (BDNF) have been implicated in some neuropsychiatric disorders. Several antipsychotic drugs affect the expression of BDNF mRNA in different areas of the rat brain. We examined the effect of single or repeated administration of 4-[4-fluorophenyl]-1,2,3,6-tetra-hydo-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842), a sigma1 receptor ligand and putative atypical antipsychotic drug on the expression of BDNF mRNA in rats. Acute treatment with E-5842 induced a down-regulation of BDNF mRNA levels in the frontal cortex and hippocampus, while a chronic treatment had no effect. Levels of another neurotrophin, nerve growth factor (NGF), remained unaltered after either acute or chronic treatment. The effects suggest that any therapeutic properties of E-5842 are not mediated by stimulation of BDNF or NGF, whereas the regulation of these trophic factors may be part of the mechanism of action of sigma1 receptor ligands.     

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

Effects of antidepressant treatment on mice lacking brain‐derived neurotrophic factor expression through promoter IV

Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.     

iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants

The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile‐like plasticity comparable to that observed during developmental critical periods: Such critical‐period‐like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug‐induced state of juvenile‐like plasticity ‘iPlasticity.’ A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain‐derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.     

Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions.

BACKGROUND: Adverse life events occurring early in development may alter the correct program of brain maturation and render the organism more vulnerable to psychiatric disorders. Identification of persistent changes associated with these events is crucial for the development of novel therapeutic strategies. METHODS: We used postnatal repeated maternal deprivation (MD) from postnatal day (PND) 2-14 to investigate changes in brain-derived neurotrophic factor (BDNF) levels. RNase protection assay and enzyme linked immunosorbent assay were employed to determine the anatomic profile of neurotrophin expression at different ages following MD. RESULTS: We found that MD produces a short-term up-regulation of neurotrophin expression in hippocampus and prefrontal cortex, as measured on PND 17, whereas at adulthood, a selective reduction of BDNF expression was observed in prefrontal cortex. When adult animals were challenged with a chronic swim stress paradigm, both a reduced expression of BDNF in prefrontal cortex and a significant reduction in striatal protein levels were found only in control subjects, whereas levels in the MD group were not further decreased. CONCLUSIONS: Our data suggest that MD produces a significant reduction of BDNF expression within prefrontal cortex and striatum, which may render these structures less plastic and more vulnerable under challenging conditions.