Chronic fluoxetine treatment in middle-aged rats induces changes in the expression of plasticity-related molecules and in neurogenesis
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 mi…
Expression of the transcription factor Pax6 in the adult rat dentate gyrus
The transcription factor Pax 6 is expressed in precursor cells during embryonic CNS development, and it plays an important role in the regulation of cell proliferation and neuronal fate determination. Pax 6-expressing cells are also present in the adult hippocampal dentate gyrus and subventricular zone/rostral migratory stream, regions in which neuronal precursors exist during adult life. In the adult dentate gyrus, precursor cells are located in the innermost portion of the granule cell layer, and Pax 6-expressing nuclei are most abundant in this region. To examine the putative role of Pax 6 in adult hippocampal neurogenesis, we have studied the proliferative activity, distribution, and ph…
Piriform cortex alterations in the Ts65Dn model for down syndrome
The piriform cortex is involved in olfactory information processing, that is altered in Down Syndrome. Moreover, piriform cortex has a crucial involvement in epilepsy generation and is one of the first regions affected in Alzheimer's Disease, both maladies being prevalent among Down Syndrome individuals. In this work, we studied the alterations in neuronal morphology, synaptology and structural plasticity in the piriform cortex of the Ts65Dn mouse model, which is the most used model for the study of this syndrome and mimics some of their alterations. We have observed that Ts65Dn piriform cortex displays: a reduction in dendritic arborisation, a higher density of inhibitory synapses (GAD67),…
Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients.
Alterations in the structure and physiology of the prefrontal cortex (PFC) have been found in different psychiatric disorders and some of them involve inhibitory networks, especially in schizophrenia and major depression. Changes in the structure of these networks may be mediated by the polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, expressed in the PFC exclusively by interneurons. Different studies have found that PSA-NCAM expression in the hippocampus and the amygdala is altered in schizophrenia, major depression and animal models of these disorders, in parallel to changes in the expression of molecules related to inhibitory …
Alterations in reelin and reelin receptors in Down syndrome.
Reelin is an extracellular matrix glycoprotein that modulates synaptic function and plasticity, with a crucial role in neuronal migration. Changes in the expression of this protein have been reported in neurodegenerative diseases, such as Alzheimer's disease (AD). This molecule is produced by Cajal-Retzius neurons during development and by inhibitory neurons in the adult nervous system. Individuals with Down syndrome (DS) present an early development of AD; therefore, we analyzed the alterations in this molecule and its receptors in the murine model for DS Ts65Dn as well as in human with DS. We performed immunofluorescence analysis for reelin and its receptors very-low-density lipoprotein r…
Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome.
Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-depe…
Chronic Fluoxetine Treatment Increases the Expression of PSA-NCAM in the Medial Prefrontal Cortex
Recent hypotheses suggest that changes in neuronal structure and connectivity may underlie the etiology of depression. The medial prefrontal cortex (mPFC) is affected by depression and shows neuronal remodeling during adulthood. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is intensely expressed in the adult mPFC. As the expression of PSA-NCAM is increased by serotonin in other cerebral regions, antidepressants acting on serotonin reuptake may influence PSA-NCAM expression and thus counteract the effects of depression by modulating neuronal structural plasticity. Using immunohistochemistry, we have studied the relationship…
The dendritic spines of interneurons are dynamic structures influenced by PSA-NCAM expression.
Excitatory neurons undergo dendritic spine remodeling in response to different stimuli. However, there is scarce information about this type of plasticity in interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is a good candidate to mediate this plasticity as it participates in neuronal remodeling and is expressed by some mature cortical interneurons, which have reduced dendritic arborization, spine density, and synaptic input. To study the connectivity of the dendritic spines of interneurons and the influence of PSA-NCAM on their dynamics, we have analyzed these structures in a subpopulation of fluorescent spiny interneurons in the hippocampus of glutamic …
Altered expression of neuropeptides in the primary somatosensory cortex of the Down syndrome model Ts65Dn.
Down syndrome is the most common genetic disorder associated with mental retardation. Subjects and mice models for Down syndrome (such as Ts65Dn) show defects in the formation of neuronal networks in both the hippocampus and the cerebral cortex. The principal neurons display alterations in the morphology, density and distribution of dendritic spines in the cortex as well as in the hippocampus. Several evidences point to the possibility that the atrophy observed in principal neurons could be mediated by changes in their inhibitory inputs and, in fact, an imbalance between excitation and inhibition has been observed in Ts65Dn mice in these regions, which are crucial for learning and informati…
The Polysialylated Form of the Neural Cell Adhesion Molecule (PSA-NCAM) Is Expressed in a Subpopulation of Mature Cortical Interneurons Characterized by Reduced Structural Features and Connectivity
Principal neurons in the adult cerebral cortex undergo synaptic, dendritic, and spine remodeling in response to different stimuli, and several reports have demonstrated that the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) participates in these plastic processes. However, there is only limited information on the expression of this molecule on interneurons and on its role in the structural plasticity of these cells. We have found that PSA-NCAM is expressed in mature interneurons widely distributed in all the extension of the cerebral cortex and have excluded the expression of this molecule in most principal cells. Although PSA-NCAM expression is generally considered a …
Differential evolution of PSA-NCAM expression during aging of the rat telencephalon
Changes in the ability of neuronal networks to undergo structural remodeling may be involved in the age-associated cognitive decline. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) declines dramatically during postnatal development, but persists in several regions of the young-adult rat telencephalon, where it participates, through its anti-adhesive properties, in neuronal structural plasticity. However, PSA-NCAM expression during aging has only been studied in the dentate gyrus and the piriform cortex layer II, where it is strongly downregulated in adult (middle-aged) individuals. Using immunohistochemistry, we have observed that in most of the telencephalic areas …
Hypocellularity in the murine model for Down Syndrome Ts65Dn is not affected by adult neurogenesis
Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity …
Role of the amygdala in antidepressant effects on hippocampal cell proliferation and survival and on depression-like behavior in the rat
The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting th…
Distribution of D2 dopamine receptor in the olfactory glomeruli of the rat olfactory bulb
Dopamine plays key roles in the processing of the olfactory information that takes place in the olfactory glomeruli. Previous studies using autoradiography demonstrate that, at the glomerular level, these actions are mainly mediated via activation of D2 dopamine receptors. Moreover, it has been suggested that D2 receptors could be present in the olfactory nerve, where they might modulate the entrance of olfactory input into the brain. Nevertheless, the precise subcellular localization of D2 receptors in the glomerular neuropil has not been investigated. In this report, we show the subcellular distribution of D2 receptors in the glomerular circuits of Wistar rats, using pre-embedding immunog…
A population of prenatally generated cells in the rat paleocortex maintains an immature neuronal phenotype into adulthood.
New neurons in the adult brain transiently express molecules related to neuronal development, such as the polysialylated form of neural cell adhesion molecule, or doublecortin (DCX). These molecules are also expressed by a cell population in the rat paleocortex layer II, whose origin, phenotype, and function are not clearly understood. We have classified most of these cells as a new cell type termed tangled cell. Some cells with the morphology of semilunar-pyramidal transitional neurons were also found among this population, as well as some scarce cells resembling semilunar, pyramidal. and fusiform neurons. We have found that none of these cells in layer II express markers of glial cells, m…
Alterations of perineuronal nets in the dorsolateral prefrontal cortex of neuropsychiatric patients
Abstract Background Alterations in the structure and physiology of interneurons in the prefrontal cortex (PFC) are important factors in the etiopathology of different psychiatric disorders. Among the interneuronal subpopulations, parvalbumin (PV) expressing cells appear to be specially affected. Interestingly, during development and adulthood the connectivity of these interneurons is regulated by the presence of perineuronal nets (PNNs), specialized regions of the extracellular matrix, which are frequently surrounding PV expressing neurons. Previous reports have found anomalies in the density of PNNs in the PFC of schizophrenic patients. However, although some studies have described alterat…
Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mPFC of Adult Rats.
Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal n…
NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons
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 …
Imaging synaptic zinc release in living nervous tissue
Zinc enriched neurons have a pool of synaptic vesicles which contain free or loosely-bound zinc ions. The movement of the vesicular zinc ions into the synaptic clefts has been previously studied by microdialysis, fluorescence postmortem staining for zinc and radioactive zinc isotope. In this study the zinc fluorescence probe N-6-metoxy-p-toluensulfonamide quinoline (TSQ) has been applied as a tracer of synaptic release of zinc ions. This fluorochrome permeates cell membranes and when exposed to living brain slices gives rise to a staining pattern similar to that seen with autometallography. In the living brain slices, fluorescence emission persists after exposure to calcium saturated ethyle…
Semilunar Granule Cells Are the Primary Source of the Perisomatic Excitatory Innervation onto Parvalbumin-Expressing Interneurons in the Dentate Gyrus
AbstractWe analyzed the origin and relevance of the perisomatic excitatory inputs on the parvalbumin interneurons of the granule cell layer in mouse. Confocal analysis of the glutamatergic innervation showed that it represents ∼50% of the perisomatic synapses that parvalbumin cells receive. This excitatory input may originate from granule cell collaterals, the mossy cells, or even supramammillary nucleus. First, we assessed the input from the mossy cells on parvalbumin interneurons. Axon terminals of mossy cells were visualized by their calretinin content. Using multicolor confocal microscopy, we observed that less than 10% of perisomatic excitatory innervation of parvalbumin cells could or…
PSA-NCAM expression in the human prefrontal cortex.
The prefrontal cortex (PFC) of adult rodents is capable of undergoing neuronal remodeling and neuroimaging studies in humans have revealed that the structure of this region also appears affected in different psychiatric disorders. However, the cellular mechanisms underlying this plasticity are still unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM participates in neurite outgrowth and synaptogenesis and changes in its expression occur parallel to neuronal remodeling in certain regions of the adult brain. PSA-NCAM is expressed in the hippocampus and temporal cortex of adult hum…