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The layer II of the adult piriform cortex (PCX) contains a numerous population of immature neurons. Interestingly, in both mice and rats, most, if not all, these cells have an embryonic origin. Moreover, recent studies from our laboratory have shown that they progressively mature into typical excitatory neurons of the PCX layer II. Therefore, the adult PCX is considered a "non-canonical" neurogenic niche. These immature neurons express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule critical for different neurodevelopmental processes. Dopamine (DA) is a relevant neurotransmitter in the adult CNS, which also plays important roles in neural development and adult plasticity, including the regulation of PSA-NCAM expression. In order to evaluate the hypothetical effects of pharmacological modulation of dopaminergic neurotransmission on the differentiation of immature neurons of the adult PCX, we studied dopamine D2 receptor (D2r) expression in this region and the relationship between dopaminergic fibers and immature neurons (defined by PSA-NCAM expression). In addition, we analyzed the density of immature neurons after chronic treatments with an antagonist and an agonist of D2r: haloperidol and PPHT, respectively. Many dopaminergic fibers were observed in close apposition to PSA-NCAM-expressing neurons, which also coexpressed D2r. Chronic treatment with haloperidol significantly increased the number of PSA-NCAM immunoreactive cells, while PPHT treatment decreased it. These results indicate a prominent role of dopamine, through D2r and PSA-NCAM, on the regulation of the final steps of development of immature neurons in the adult PCX. [ABSTRACT FROM AUTHOR]

Chronic stress has an important impact on the adult brain. However, most of the knowledge on its effects is focused on principal neurons and less on inhibitory neurons. Consequently, recent reports have begun to describe stress-induced alterations in the structure, connectivity and neurochemistry of interneurons. Some of these changes appear to be mediated by certain molecules particularly associated to interneurons, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and components of the perineuronal nets (PNN), specialized regions of the extracellular matrix. These plasticity-related molecules modulate interneuronal structure and connectivity, particularly of parvalbumin expressing basket interneurons, both during development and adult life. These inhibitory neurons are specially affected after chronic stress and in some stress-related disorders, in which the expression of PSA-NCAM and certain components of PNN are also altered. For these reasons we have decided to study PSA-NCAM, PNN and parvalbumin expressing interneurons after 10 days of chronic restraint stress, a time point in which its behavioral consequences are starting to appear. We have focused initially on the medial prefrontal cortex (mPFC), basolateral amygdala (BLA) and hippocampus, regions affected by stress and stress-related psychiatric diseases, but we have also explored the habenula and the thalamic reticular nucleus (TRN) due to the important presence of PNN and their relationship with certain disorders. PSA-NCAM expression was increased by stress in the stratum lacunosum-moleculare of CA1. Increases in parvalbumin immunoreactive cells were detected in the mPFC and the BLA, but were not accompanied by increases in the number of parvalbumin expressing perisomatic puncta on the somata of principal neurons. The number of PNN was also increased in the mPFC and the habenula, although habenular PNN were not associated to parvalbumin cells. Increased expression of parvalbumin and components of PNN were also detected in the TRN after chronic restraint stress, revealing for the first time substantial effects on this region. Our study shows that, even a short chronic stress protocol, can induce consistent changes in interneuronal plasticity-related molecules in cortical and extracortical regions, which may represent initial responses of inhibitory circuits to counteract the effects of this aversive experience. [ABSTRACT FROM AUTHOR]

The structure and function of the medial prefrontal cortex (mPFC) is affected in several neuropsychiatric disorders, including schizophrenia and major depression. Recent studies suggest that imbalances between excitatory and inhibitory activity (E/I) may be responsible for this cortical dysfunction and therefore, may underlie the core symptoms of these diseases. This E/I imbalance seems to be correlated with alterations in the plasticity of interneurons but there is still scarce information on the mechanisms that may link these phenomena. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a good candidate, because it modulates the neuronal plasticity of interneurons and its expression is altered in schizophrenia and major depression. To address this question, we have developed an in vitro model using mPFC organotypic cultures of transgenic mice displaying fluorescent spiny interneurons. After enzymatic depletion of PSA, the spine density of interneurons, the number of synaptic puncta surrounding pyramidal neuron somata and the E/I ratio were strongly affected. These results point to the polysialylation of NCAM as an important factor in the maintenance of E/I balance and the structural plasticity of interneurons. This may be particularly relevant for better understanding the etiology of schizophrenia and major depression. [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]

The polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) is expressed by immature neurons in the amygdala of adult mammals, including non-human primates. In a recent report we have also described the presence of PSA-NCAM-expressing cells in the amygdala of adult humans. Although many of these cells have been classified as mature interneurons, some of them lacked mature neuronal markers, suggesting the presence of immature neurons. We have studied, using immunohistochemistry, the existence and distribution of these immature neurons using post mortem material. We have also analysed the presence of proliferating cells and the association between immature neurons and specialised astrocytes. These parameters have also been studied for comparative purposes in the amygdalae of cats and squirrel monkeys. Our results demonstrate that cells coexpressing doublecortin and PSA-NCAM, but lacking neuronal nuclear antigen expression, were present in the amygdala of adult humans. These cells were organised in elongated clusters, which were located between the white matter of the dorsal hippocampus and the basolateral amygdaloid nucleus. These clusters were not associated with astroglial specialised structures. No cells expressing the proliferative marker Ki67 were observed in the amygdaloid parenchyma, although some of them were found in the vicinity of the lateral ventricle. Immature neurons were also present in the amygdala of squirrel monkeys and cats. These cells also appeared clustered in monkeys, although not as organised as in humans. In cats these cells are scarce, appear isolated and most of the PSA-NCAM-expressing structures corresponded to processes apparently originating from the paleocortical layer II. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian central nervous system, due to its interaction with the environment, must be endowed with plasticity. Conversely, the nervous tissue must be substantially static to ensure connectional invariability. Structural plasticity can be viewed as a compromise between these requirements. In adult mammals, brain structural plasticity is strongly reduced with respect to other animal groups in the phylogenetic tree. It persists under different forms, which mainly consist of remodeling of neuronal shape and connectivity, and, to a lesser extent, the production of new neurons. Adult neurogenesis is mainly restricted within two neurogenic niches, yet some gliogenic and neurogenic processes also occur in the so-called non-neurogenic tissue, starting from parenchymal progenitors. In this review we focus on a population of immature, non-newly generated neurons in layer II of the cerebral cortex, which were previously thought to be newly generated since they heavily express the polysialylated form of the neural cell adhesion molecule and doublecortin. These unusual neurons exhibit characteristics defining an additional type of structural plasticity, different from either synaptic plasticity or adult neurogenesis. Evidences concerning their morphology, antigenic features, ultrastructure, phenotype, origin, fate, and reaction to different kind of stimulations are gathered and analyzed. Their possible role is discussed in the context of an enriched complexity and heterogeneity of mammalian brain structural plasticity. [Copyright &y& Elsevier]

Abstract Doublecortin (DCX) is a protein required for normal neuronal migration in the developing cerebral cortex, where it is widely expressed in both radially and tangentially migrating neuroblasts. Moreover, it has been observed in the adult rostral migratory stream, which contains the neuronal precursors traveling to the olfactory bulb. We have performed DCX immunocytochemistry in the adult rat brain to identify precisely the neuronal populations expressing this protein. Our observations confirm the presence of DCX immunoreactive cells with the characteristic morphology of migrating neuroblasts in the subventricular zone, rostral migratory stream and the main and accessory olfactory bulbs. We have also found putative migratory cells expressing DCX in regions were no adult neuronal migration has been described, as the corpus callosum, the piriform cortex layer III/endopiriform nucleus and the striatum. Surprisingly, many cells with the phenotype of differentiated neurons were DCX immunoreactive; e.g. certain granule neurons in the hilar border of the granular layer of the dentate gyrus, some neuronal types in the piriform cortex layer II, granule and periglomerular neurons in the main and accessory olfactory bulbs, and isolated cells in the striatum. Almost all DCX immunoreactive cells also express the polysialylated form of neural cell adhesion molecule and have a similar distribution to rat collapsin receptor-mediated protein-4, two molecules involved in neuronal structural plasticity. Given these results, we hypothesize that DCX expression in differentiated neurons could be related to its capacity for microtubule reorganization and that this fact could be linked to axonal outgrowth or synaptogenesis. [ABSTRACT FROM AUTHOR]

Abstract During adulthood, neural precursors located in the subgranular zone of the dentate gyrus continue to proliferate, leading to the generation of new granule neurons. These recently generated cells transiently express the polysialylated form of the neural cell adhesion molecule, PSA-NCAM, and are supported by radial glia-like cells that are likely to play a role in neuronal migration and differentiation, or even act as their precursors. Previous reports indicate that treatment with NMDA receptor antagonists stimulates adult neurogenesis in the dentate gyrus, and because of the potential therapeutic value of this approach, we were interested in further characterizing the consequences of pharmacologically modulating this process. We treated adult rats with the competitive NMDA receptor antagonist, CGP43487, and examined cell proliferation, PSA-NCAM expression, and changes in the radial glia cell population in the subgranular zone at different time points. In addition, we sought to determine if this treatment led to changes in cell death or gliotic reactions. The number of proliferating cells in the subgranular region of the dentate gyrus was increased significantly 2 days after treatment and it remained elevated 7 days postinjection. PSA-NCAM-immunoreactive granule cells and nestin-expressing radial glia-like cells also increased in number 7 days after the treatment. In contrast, we did not observe any change in granule cell death, and we were unable to detect any microglial or astroglial reaction during the first 7 days after treatment. Thus, NMDA receptor antagonist treatment serves as a valuable tool to increase neurogenesis in the adult hippocampus without undesirable collateral deleterious effects. [ABSTRACT FROM AUTHOR]

Immature neurons are maintained in cortical regions of the adult mammalian brain. In rodents, many of these immature neurons can be identified in the piriform cortex based on their high expression of early neuronal markers, such as doublecortin (DCX) and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule plays critical roles in different neurodevelopmental events. Taking advantage of a DCX-CreERT2/Flox-EGFP reporter mice, we investigated the impact of targeted PSA enzymatic depletion in the piriform cortex on the fate of immature neurons. We report here that the removal of PSA accelerated the final development of immature neurons. This was revealed by a higher frequency of NeuN expression, an increase in the number of cells carrying an axon initial segment (AIS), and an increase in the number of dendrites and dendritic spines on the immature neurons. Taken together, our results demonstrated the crucial role of the PSA moiety in the protracted development of immature neurons residing outside of the neurogenic niches. More studies will be required to understand the intrinsic and extrinsic factors affecting PSA-NCAM expression to understand how the brain regulates the incorporation of these immature neurons to the established neuronal circuits of the adult brain. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Occurrence of new neurons in the piriform cortex" by T. F. Yuan and colleagues.

Abstract: Chronic immobilization stress (CIS) shortens apical dendritic trees of CA3 pyramidal neurons in the hippocampus of the male rat, and dendritic length may be a determinant of vulnerability to stress. Expression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the hippocampal formation is increased by stress, while PSA removal by Endo-neuraminidase-N (endo-N) is known to cause the mossy fibers to defasciculate and synapse ectopically in their CA3 target area. We show here that enzymatic removal of PSA produced a remarkable expansion of dendritic arbors of CA3 pyramidal neurons, with a lesser effect in CA1. This expansion eclipsed the CIS-induced shortening of CA3 dendrites, with the expanded dendrites of both no-stress-endo-N and CIS-endo-N rats being longer than those in no-stress-control rats and much longer than those in CIS-control rats. As predicted by the hypothesis that endo-N-induced dendritic expansion might increase vulnerability to excitotoxic challenge, systemic injection with kainic acid, showed markedly increased neuronal degeneration, as assessed by fluorojade B histochemistry, in rats that had been treated with endo-N compared to vehicle-treated rats throughout the entire hippocampal formation. PSA removal also exacerbated the CIS-induced reduction in body weight and abolished effects of CIS on NPY and NR2B mRNA levels. These findings support the hypothesis that CA3 arbor plasticity plays a protective role during prolonged stress and clarify the role of PSA-NCAM in stress-induced dendritic plasticity. [Copyright &y& Elsevier]

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]

Introduction Chronic stress induces dendritic atrophy and decreases spine density in excitatory hippocampal neurons, although there is also ample evidence indicating that the GABAergic system is altered in the hippocampus after this aversive experience. Chronic stress causes dendritic remodeling both in excitatory neurons and interneurons in the medial prefrontal cortex and the amygdala. Methods In order to know whether it also has an impact on the structure and neurotransmission of hippocampal interneurons, we have analyzed the dendritic arborization, spine density, and the expression of markers of inhibitory synapses and plasticity in the hippocampus of mice submitted to 21 days of mild restrain stress. The analyses were performed in GIN mice, a strain that displays EGFP-labeled interneurons. Results We observed a significant decrease in the dendritic arborization of interneurons in the CA1 region, which did not occur in those in CA3. We found neither changes in dendritic spine density in these regions nor alterations in the number of EGFP-positive interneurons. Nevertheless, the expression of glutamic acid decarboxylase 67 was reduced in different layers of CA1 and CA3 regions of the hippocampus. No significant changes were found in the expression of the polysialylated form of the neural cell adhesion molecule ( PSA- NCAM) or synaptophysin. Conclusions Chronic stress reduces the interneuronal dendritic arborization in CA1 region of the hippocampus but not in CA3. [ABSTRACT FROM AUTHOR]

Abstract: Neuroimaging has revealed structural abnormalities in the amygdala of different psychiatric disorders. The polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, which expression is altered in schizophrenia, major depression and in animal models of these disorders, may participate in these changes. However, PSA-NCAM has not been studied in the human amygdala. To know whether its expression and that of presynaptic markers, was affected in psychiatric disorders, we have analyzed post-mortem sections from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. PSA-NCAM was expressed in neuronal somata and neuropil puncta, many of which corresponded to interneurons. Depressed patients showed decreases in PSA-NCAM expression in the basolateral and basomedial amygdala; synaptophysin and GAD67 were also decreased, while VGLUT-1 was increased, in different nuclei. Increases in PSA-NCAM expression were found in the lateral nucleus of bipolar patients; synaptophysin and GAD67 were reduced, and VGLUT-1 increased, in their basolateral and lateral nuclei. The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. These results indicate that inhibitory and excitatory amygdaloid circuits are affected in these disorders and that abnormal PSA-NCAM expression in depressive and bipolar patients may underlie these alterations. [Copyright &y& Elsevier]