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The estrous cycle is caused by the changing concentration of ovarian hormones, particularly 17β-estradiol, a hormone whose effect on excitatory circuits has been extensively reported. However, fewer studies have tried to elucidate how this cycle, or this hormone, affects the plasticity of inhibitory networks and the structure of interneurons. Among these cells, somatostatin-expressing O-LM neurons of the hippocampus are especially interesting. They have a role in the modulation of theta oscillations, and they receive direct input from the entorhinal cortex, which place them in the center of hippocampal function. In this study, we report that the expression of polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the hippocampus, a molecule involved in the plasticity of somatostatin-expressing interneurons in the adult brain, fluctuated through the different stages of the estrous cycle. Likewise, these stages and the expression of PSA-NCAM affected the density of dendritic spines of O-LM cells. We also describe that 17β-estradiol replacement of adult ovariectomized female mice caused an increase in the perisomatic inhibitory puncta in O-LM interneurons as well as an increase in their axonal bouton density. Interestingly, this treatment also induced a decrease in their dendritic spine density, specifically in O-LM interneurons lacking PSA-NCAM expression. Finally, using an ex vivo real-time assay with entorhinal-hippocampal organotypic cultures, we show that this hormone decreased the dynamics in spinogenesis, altogether highlighting the modulatory effect that 17β-estradiol has on inhibitory circuits. [ABSTRACT FROM AUTHOR]

Abstract Background Antidepressants promote neuronal structural plasticity in young-adult rodents, but little is known of their effects on older animals. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM is expressed in immature neurons and in a subpopulation of mature interneurons and its expression is modulated by antidepressants in the telencephalon of young-adult rodents. Results We have analyzed the effects of 14 days of fluoxetine treatment on the density of puncta expressing PSA-NCAM and different presynaptic markers in the medial prefrontal cortex, hippocampus and amygdala of middle-aged (8 months old) rats. The density of puncta expressing PSA-NCAM increased in the dorsal cingulate cortex, as well as in different hippocampal and amygdaloid regions. In these later regions there were also increases in the density of puncta expressing glutamic acid decarboxylase 65/67 (GAD6), synaptophysin (SYN), PSA-NCAM/SYN and PSA-NCAM/GAD6, but a decrease of those expressing vesicular glutamate transporter 1 (VGluT1). Since there is controversy on the effects of antidepressants on neurogenesis during aging, we analyzed the number of proliferating cells expressing Ki67 and that of immature neurons expressing doublecortin or PSA-NCAM. No significant changes were found in the subgranular zone, but the number of proliferating cells decreased in the subventricular zone. Conclusions These results indicate that the effects of fluoxetine in middle-aged rats are different to those previously described in young-adult animals, being more restricted in the mPFC and even following an opposite direction in the amygdala or the subventricular zone.

Parvalbumin-expressing (PV+) interneurons play a key role in the maturation and synchronization of cortical circuitry and alterations in these inhibitory neurons, especially in the medial prefrontal cortex (mPFC), have been found in different psychiatric disorders. The formation of perineuronal nets (PNNs) around many of these interneurons at the end of the critical periods reduces their plasticity and sets their connectivity. Consequently, the presence of PNNs must have an important impact on the synaptic input and the physiology of PV + cells. In the present study, we have found that in adult male mice, prefrontocortical PV+ cells surrounded by PNNs show higher density of perisomatic excitatory and inhibitory puncta, longer axonal initial segments (AISs), and higher PV expression when compared with PV+ cells lacking PNNs. In order to better understand the impact of PNNs on the connectivity and physiology of PV+ interneurons in the mPFC, we have digested enzymatically these structures and have found a decrease in the density of inhibitory puncta on their perisomatic region but not on the PV+ perisomatic puncta on pyramidal neurons. Moreover, extracellular recordings show that the digestion of PNNs induces a decrease in y activity, an oscillation dependent on PV+ cells, in the mPFC of anesthetized mice. Our results suggest that the presence of PNNs enwrapping PV+ cells regulates their inhibitory input and has a potent influence on their activity. These results may be relevant for psychiatric research, given the alterations in PNNs, PV+ interneurons and their physiology described in different mental disorders. [ABSTRACT FROM AUTHOR]

Several experimental manipulations, including visual deprivation, are able to induce critical period‐like plasticity in the visual cortex of adult animals. In this regard, many studies have analyzed the effects of dark exposure in adult animals, but still little is known about the role of interneurons and plasticity‐related molecules on such mechanisms. In this study, we analyzed the effects of 10 days of dark exposure on the connectivity and structure of interneurons, both in the primary visual cortex and in the rest of cerebral regions implicated in the transmission of visual stimulus. We found that this environmental manipulation induces changes in the expression of synaptic molecules throughout the visual pathway and in the structure of interneurons in the primary visual cortex. Moreover, we found altered expression in the polysialylated form of the neural cell adhesion molecule and in perineuronal nets surrounding parvalbumin expressing interneurons, suggesting that these plasticity‐related molecules may be involved in the changes produced by dark exposure. Together, our findings indicate that dark exposure produces an important alteration of inhibitory circuits and molecules related to their plasticity, not only in the visual cortex but throughout the visual pathway. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA). Both areas are well-known regulators of the reward-based decision-making process and hence likely to be involved in processes like evidence integration, impulsivity or addiction biology, but also in helping us to predict the valence of our future actions: i.e., what is "good" and what is "bad." Here we propose a hypothesis of a critical period, during which the inputs of the mPFC compete for target innervation, establishing specific prefrontal network configurations in the adult brain. We discuss how these different prefrontal configurations are linked to brain diseases such as addiction or neuropsychiatric disorders, and especially how drug abuse and other events during early life stages might lead to the formation of more vulnerable prefrontal network configurations. Finally, we show different promising pharmacological approaches that, when combined with the appropriate stimuli, will be able to re-establish these functional prefrontocortical configurations during adulthood. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB). We have also used entorhinohippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders. [ABSTRACT FROM AUTHOR]

Reelin, a glycoprotein expressed by Cajal-Retzius neurons throughout the marginal layer of developing neocortex, has been extensively shown to play an important role during brain development, guiding neuronal migration and detachment from radial glia. During the adult life, however, many studies have associated Reelin expression to enhanced neuronal plasticity. Although its mechanism of action in the adult brain remains mostly unknown, Reelin is expressed mainly by a subset of mature interneurons. Here, we confirm the described phenotype of this subpopulation in the adult neocortex. We show that these mature interneurons, although being in close proximity, lack polysialylated neural cell adhesion molecule (PSA-NCAM) expression, a molecule expressed by a subpopulation of mature interneurons, related to brain development and involved in neuronal plasticity of the adult brain as well. However, in the layer II of Piriform cortex there is a high density of cells expressing Reelin whose neurochemical phenotype and connectivity has not been described before. Interestingly, in close proximity to these Reelin expressing cells there is a numerous subpopulation of immature neurons expressing PSA-NCAM and doublecortin (DCX) in this layer of the Piriform cortex. Here, we show that Reelin cells express the neuronal marker Neuronal Nuclei (NeuN), but however the majority of neurons lack markers of mature excitatory or inhibitory neurons. A detail analysis of its morphology indicates these that some of these cells might correspond to semilunar neurons. Interestingly, we found that the majority of these cells express T-box brain 1 (TBR-1) a transcription factor found not only in post-mitotic neurons that differentiate to glutamatergic excitatory neurons but also in Cajal-Retzius cells. We suggest that the function of these Reelin expressing cells might be similar to that of the Cajal-Retzius cells during development, having a role in the maintenance of the immature phenotype of the PSA-NCAM/DCX neurons through its receptors apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) in the Piriform cortex layer II during adulthood. [ABSTRACT FROM AUTHOR]

Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenilelike plasticity triggered by Fluoxetine. [ABSTRACT FROM AUTHOR]

Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plast2city induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain. [ABSTRACT FROM AUTHOR]

Neuroligins (NLGNs) are cell adhesion molecules that are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I). Mutations in NLGNs have been linked to psychiatric disorders in humans involving social dysfunction and are related to similar abnormalities in animal models. Chronic stress increases the likelihood for affective disorders and has been shown to induce changes in neural structure and function in different brain regions, with the hippocampus being highly vulnerable to stress. Previous studies have shown evidence of chronic stress-induced changes in the neural E/I balance in the hippocampus. Therefore, we hypothesized that chronic restraint stress would lead to reduced hippocampal NLGN-2 levels, in association with alterations in social behavior. We found that rats submitted to chronic restraint stress in adulthood display reduced sociability and increased aggression. This occurs along with a reduction of NLGN-2, but not NLGN-1 expression (as shown with western blot, immunohistochemistry, and electron microscopy analyses), throughout the hippocampus and detectable in different layers of the CA1, CA3, and DG subfields. Furthermore, using synthetic peptides that comprise sequences in either NLGN-1 (neurolide-1) or NLGN-2 (neurolide-2) involved in the interaction with their presynaptic partner neurexin (NRXN)-1, intra-hippocampal administration of neurolide-2 led also to reduced sociability and increased aggression. These results highlight hippocampal NLGN-2 as a key molecular substrate regulating social behaviors and underscore NLGNs as promising targets for the development of novel drugs for the treatment of dysfunctional social behaviors. [ABSTRACT FROM AUTHOR]

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain. [ABSTRACT FROM AUTHOR]

Background: Antidepressants promote neuronal structural plasticity in young-adult rodents, but little is known of their effects on older animals. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM is expressed in immature neurons and in a subpopulation of mature interneurons and its expression is modulated by antidepressants in the telencephalon of young-adult rodents. Results: We have analyzed the effects of 14 days of fluoxetine treatment on the density of puncta expressing PSANCAM and different presynaptic markers in the medial prefrontal cortex, hippocampus and amygdala of middleaged (8 months old) rats. The density of puncta expressing PSA-NCAM increased in the dorsal cingulate cortex, as well as in different hippocampal and amygdaloid regions. In these later regions there were also increases in the density of puncta expressing glutamic acid decarboxylase 65/67 (GAD6), synaptophysin (SYN), PSA-NCAM/SYN and PSA-NCAM/GAD6, but a decrease of those expressing vesicular glutamate transporter 1 (VGluT1). Since there is controversy on the effects of antidepressants on neurogenesis during aging, we analyzed the number of proliferating cells expressing Ki67 and that of immature neurons expressing doublecortin or PSA-NCAM. No significant changes were found in the subgranular zone, but the number of proliferating cells decreased in the subventricular zone. Conclusions: These results indicate that the effects of fluoxetine in middle-aged rats are different to those previously described in young-adult animals, being more restricted in the mPFC and even following an opposite direction in the amygdala or the subventricular zone. [ABSTRACT FROM AUTHOR]

Although the precise mechanism of action of antidepressant drugs remains elusive, the neuroplastic hypothesis has gained acceptance during the last two decades. Several studies have shown that treatment with antidepressants such as Fluoxetine is associated with enhanced plasticity in control animals, especially in regions such as the visual cortex, the hippocampus and the medial prefrontal cortex. More recently, the basolateral amygdala has been shown to be affected by Fluoxetine leading to a reopening of critical period-like plasticity in the fear and aggression circuits. One of the key elements triggering this type of brain plasticity are inhibitory networks, especially parvalbumin interneurons. However, recent work on fast-acting antidepressants has shown also an important role for somatostatin interneurons. Here we show that Fluoxetine reorganizes inhibitory circuits through increased expression of the plasticity-related molecule PSA-NCAM which regulates interneuronal structure and connectivity. In addition, we demonstrate that treatment with this antidepressant alters the structure of somatostatin interneurons both at the level of dendritic spines and of axonal en passant boutons . Our findings suggest that new strategies targeting somatostatin interneuron activity might help us to better understand depression and the action of antidepressants. [ABSTRACT FROM AUTHOR]

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization-resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC, suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression.

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.