Postnatal fluoxetine treatment alters perineuronal net formation and maintenance in the hippocampus

AbstractElevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day 21 in Sprague-Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal parvalbumin, calretinin, or reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the developmental trajectory of PNNs within the hippocampus, raising the possibility of a disruption of critical period plasticity and the establishment of an altered excitation-inhibition balance within this key limbic brain region.Significance StatementClinical and preclinical studies indicate that developmental exposure to fluoxetine programs persistent dysregulation of mood-related behaviors. This is hypothesized to involve the disruption of the normal development of key brain regions, such as the hippocampus that regulate mood behaviors. We show that postnatal exposure to fluoxetine alters hippocampal perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity and mark the closure of critical periods. The decline in PNNs is noted in early postnatal life, and persists into adulthood in specific hippocampal subfields. Adult animals with a history of postnatal fluoxetine exposure exhibit altered numbers of somatostatin interneurons, GABA receptor subunit expression and neuronal activation within the hippocampus. This indicates that postnatal fluoxetine disrupts the normal developmental trajectory of the hippocampus.

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An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity

International Journal of Molecular Sciences ◽

10.3390/ijms22052434 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2434

Author(s):

Daniela Carulli ◽

Joost Verhaagen

Keyword(s):

Critical Period ◽

Brain Plasticity ◽

Time Windows ◽

Adult Brain ◽

Mammalian Brain ◽

Postnatal Life ◽

Perineuronal Nets ◽

Critical Periods ◽

Perineuronal Net ◽

Memory Processes

During restricted time windows of postnatal life, called critical periods, neural circuits are highly plastic and are shaped by environmental stimuli. In several mammalian brain areas, from the cerebral cortex to the hippocampus and amygdala, the closure of the critical period is dependent on the formation of perineuronal nets. Perineuronal nets are a condensed form of an extracellular matrix, which surrounds the soma and proximal dendrites of subsets of neurons, enwrapping synaptic terminals. Experimentally disrupting perineuronal nets in adult animals induces the reactivation of critical period plasticity, pointing to a role of the perineuronal net as a molecular brake on plasticity as the critical period closes. Interestingly, in the adult brain, the expression of perineuronal nets is remarkably dynamic, changing its plasticity-associated conditions, including memory processes. In this review, we aimed to address how perineuronal nets contribute to the maturation of brain circuits and the regulation of adult brain plasticity and memory processes in physiological and pathological conditions.

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Perineuronal Net Dynamics in the Pathophysiology of Epilepsy

Epilepsy Currents ◽

10.1177/15357597211018688 ◽

2021 ◽

pp. 153575972110186

Author(s):

Lata Chaunsali ◽

Bhanu P. Tewari ◽

Harald Sontheimer

Keyword(s):

Critical Period ◽

Seizure Activity ◽

Perineuronal Nets ◽

Rodent Models ◽

Central Nervous System Diseases ◽

Intrinsic Properties ◽

Perineuronal Net ◽

Ecm Remodeling ◽

Activity Inhibition ◽

Wide Range

Perineuronal nets (PNNs) are condensed extracellular matrix (ECM) assemblies of polyanionic chondroitin sulfate proteoglycans, hyaluronan, and tenascins that primarily wrap around GABAergic parvalbumin (PV) interneurons. During development, PNN formation terminates the critical period of neuroplasticity, a process that can be reversed by experimental disruption of PNNs. Perineuronal nets also regulate the intrinsic properties of the enclosed PV neurons thereby maintaining their inhibitory activity. Recent studies have implicated PNNs in central nervous system diseases as well as PV neuron dysfunction; consequently, they have further been associated with altered inhibition, particularly in the genesis of epilepsy. A wide range of seizure presentations in human and rodent models exhibit ECM remodeling with PNN disruption due to elevated protease activity. Inhibition of PNN proteolysis reduces seizure activity suggesting that PNN degrading enzymes may be potential novel therapeutic targets.

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Otx2-PNN Interaction to Regulate Cortical Plasticity

Neural Plasticity ◽

10.1155/2016/7931693 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 40

Author(s):

Clémence Bernard ◽

Alain Prochiantz

Keyword(s):

Extracellular Matrix ◽

Visual Cortex ◽

Binocular Vision ◽

Critical Period ◽

Cortical Plasticity ◽

Inhibitory Interneurons ◽

Perineuronal Nets ◽

Critical Periods ◽

Cortical Function ◽

Parvalbumin Interneurons

The ability of the environment to shape cortical function is at its highest during critical periods of postnatal development. In the visual cortex, critical period onset is triggered by the maturation of parvalbumin inhibitory interneurons, which gradually become surrounded by a specialized glycosaminoglycan-rich extracellular matrix: the perineuronal nets. Among the identified factors regulating cortical plasticity in the visual cortex, extracortical homeoprotein Otx2 is transferred specifically into parvalbumin interneurons and this transfer regulates both the onset and the closure of the critical period of plasticity for binocular vision. Here, we review the interaction between the complex sugars of the perineuronal nets and homeoprotein Otx2 and how this interaction regulates cortical plasticity during critical period and in adulthood.

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Chondroitin 6-Sulfation Regulates Perineuronal Net Formation by Controlling the Stability of Aggrecan

Neural Plasticity ◽

10.1155/2016/1305801 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Shinji Miyata ◽

Hiroshi Kitagawa

Keyword(s):

Extracellular Matrix ◽

Chondroitin Sulfate ◽

Neural Plasticity ◽

Adult Brain ◽

Chondroitin Sulfate Proteoglycans ◽

Perineuronal Nets ◽

Perineuronal Net ◽

A Disintegrin And Metalloproteinase ◽

The Stability ◽

Thrombospondin Motif

Perineuronal nets (PNNs) are lattice-like extracellular matrix structures composed of chondroitin sulfate proteoglycans (CSPGs). The appearance of PNNs parallels the decline of neural plasticity, and disruption of PNNs reactivates neural plasticity in the adult brain. We previously reported that sulfation patterns of chondroitin sulfate (CS) chains on CSPGs influenced the formation of PNNs and neural plasticity. However, the mechanism of PNN formation regulated by CS sulfation remains unknown. Here we found that overexpression of chondroitin 6-sulfotransferase-1 (C6ST-1), which catalyzes 6-sulfation of CS chains, selectively decreased aggrecan, a major CSPG in PNNs, in the aged brain without affecting other PNN components. Both diffuse and PNN-associated aggrecans were reduced by overexpression of C6ST-1. C6ST-1 increased 6-sulfation in both the repeating disaccharide region and linkage region of CS chains. Overexpression of 6-sulfation primarily impaired accumulation of aggrecan in PNNs, whereas condensation of other PNN components was not affected. Finally, we found that increased 6-sulfation accelerated proteolysis of aggrecan by a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) protease. Taken together, our results indicate that sulfation patterns of CS chains on aggrecan influenced the stability of the CSPG, thereby regulating formation of PNNs and neural plasticity.

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The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽

10.3390/cells10051046 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1046

Author(s):

Jorge Martinez ◽

Patricio C. Smith

Keyword(s):

Extracellular Matrix ◽

Type I Collagen ◽

Cell Metabolism ◽

Breast Tumors ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Desmoplastic Reaction ◽

The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

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Cell-derived Extracellular Matrix as maintaining Biomaterial for adipogenic differentiation

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2020-3106 ◽

2020 ◽

Vol 6 (3) ◽

pp. 410-413

Author(s):

Petra J. Kluger ◽

Svenja Nellinger ◽

Simon Heine ◽

Ann-Cathrin Volz

Keyword(s):

Tissue Engineering ◽

Extracellular Matrix ◽

Adipogenic Differentiation ◽

Cellular Activity ◽

Adipose Tissue Engineering ◽

Physical Support ◽

Supporting Effect ◽

Brdu Assay ◽

The Impact

AbstractThe extracellular matrix (ECM) naturally surrounds cells in humans, and therefore represents the ideal biomaterial for tissue engineering. ECM from different tissues exhibit different composition and physical characteristics. Thus, ECM provides not only physical support but also contains crucial biochemical signals that influence cell adhesion, morphology, proliferation and differentiation. Next to native ECM from mature tissue, ECM can also be obtained from the in vitro culture of cells. In this study, we aimed to highlight the supporting effect of cell-derived- ECM (cdECM) on adipogenic differentiation. ASCs were seeded on top of cdECM from ASCs (scdECM) or pre-adipocytes (acdECM). The impact of ECM on cellular activity was determined by LDH assay, WST I assay and BrdU assay. A supporting effect of cdECM substrates on adipogenic differentiation was determined by oil red O staining and subsequent quantification. Results revealed no effect of cdECM substrates on cellular activity. Regarding adipogenic differentiation a supporting effect of cdECM substrates was obtained compared to control. With these results, we confirm cdECM as a promising biomaterial for adipose tissue engineering.

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Adolescence as a “critical period” in the heritage language use. Polish in Germany

Open Linguistics ◽

10.1515/opli-2021-0019 ◽

2021 ◽

Vol 7 (1) ◽

pp. 301-315

Author(s):

Hanna Pułaczewska

Keyword(s):

Role Models ◽

Personal Development ◽

Critical Period ◽

Growing Up ◽

Age Related ◽

The Media ◽

Role Of Parents ◽

Qualitative Part ◽

The Impact

Abstract In the article, we consider the impact of adolescence upon the usage of Polish in Polish-German bilinguals raised and living in Germany and demonstrate how adolescence surfaces as a socially based “critical period” in this usage using results from a survey and interviews conducted with 30 teenagers. In the quantitative part of the study, we seek to establish whether adolescents’ age affected the pattern and quantity of their usage of Polish in the media and contacts with age peers, whether the latter two facets of growing up with Polish were interrelated, and which other factors affected peer-relevant activities in Polish. Both age and peer contact turned out to significantly affect the use of the media in Polish, while peer contact in Polish was affected by the parental use of Polish in parent-child communication. The qualitative part presents the context and motivation for using Polish by the youths in peer-relevant activities. We integrate the results with insights provided by child development psychology from the perspective of language socialisation theory and interpret the age-related decline of interest in the Polish media as an effect of a diminishing role of parents and the increasing role of age peers as role models in personal development.

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How Did Prenatal Education Impact Women’s Perception of Pregnancy and Postnatal Life in a Romanian Population

Medicina ◽

10.3390/medicina57060581 ◽

2021 ◽

Vol 57 (6) ◽

pp. 581

Author(s):

Anca Maria Balasoiu ◽

Octavian Gabriel Olaru ◽

Romina Marina Sima ◽

Liana Ples

Keyword(s):

Prenatal Care ◽

Newborn Care ◽

Control Group ◽

Postnatal Life ◽

Study Group ◽

Prenatal Education ◽

Questionnaire Online ◽

A Prospective Study ◽

The Impact ◽

Official Information

Background and Objectives: Prenatal education represents an important part of maternal prenatal care in Western countries. In Romania, prenatal education is of recent interest but there is no official information about prenatal courses and their impact on prenatal care and patients in Romania. Material and methods: A prospective study based on the STROBE statement was designed in order to assess the prenatal education delivered in our unit. The study group included women who gave birth at Bucur Maternity, “Saint. John” Hospital, Bucharest, Romania and attended the prenatal courses, compared with a control group (women who gave birth in our unit but did not attend the prenatal lecture). Patients’ perception about the impact of prenatal education was collected by applying a questionnaire. Results: The analysis included 89 women who fulfilled the questionnaire online. In our study, 62 women (69.7%) attended the prenatal education classes and represented the study group while 27 women (30.3%) constituted the control group. Women who attended the prenatal lecture recognized the utility of the topic regarding newborn care (90.3%), while women from the control group did not consider it useful (n = 55.6%), χ2 = 18.412, p < 0.001. Patients from the study group admitted the importance of the topics (93.5%) from the lectures about breast feeding, while the percentage of these women from the control group is significantly lower (55.6%) χ2 = 27.867, p < 0.001. Conclusions: The benefits of prenatal education were recognized by women who attended the prenatal lecture, while women who did not participate underestimated the utility of the topics. Further actions are required to inform mothers about the necessity of antenatal education.

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Adjustment of Whey:Casein Ratio from 20:80 to 60:40 in Milk Formulation Affects Food Intake and Brainstem and Hypothalamic Neuronal Activation and Gene Expression in Laboratory Mice

Foods ◽

10.3390/foods10030658 ◽

2021 ◽

Vol 10 (3) ◽

pp. 658

Author(s):

Erin L. Wood ◽

David G. Christian ◽

Mohammed Arafat ◽

Laura K. McColl ◽

Colin G. Prosser ◽

...

Keyword(s):

Food Intake ◽

Area Postrema ◽

Energy Levels ◽

Early Gene ◽

Hypothalamic Nucleus ◽

Laboratory Mice ◽

Neuronal Activation ◽

Short Term ◽

Animal Milk ◽

The Impact

Adjustment of protein content in milk formulations modifies protein and energy levels, ensures amino acid intake and affects satiety. The shift from the natural whey:casein ratio of ~20:80 in animal milk is oftentimes done to reflect the 60:40 ratio of human milk. Studies show that 20:80 versus 60:40 whey:casein milks differently affect glucose metabolism and hormone release; these data parallel animal model findings. It is unknown whether the adjustment from the 20:80 to 60:40 ratio affects appetite and brain processes related to food intake. In this set of studies, we focused on the impact of the 20:80 vs. 60:40 whey:casein content in milk on food intake and feeding-related brain processes in the adult organism. By utilising laboratory mice, we found that the 20:80 whey:casein milk formulation was consumed less avidly and was less preferred than the 60:40 formulation in short-term choice and no-choice feeding paradigms. The relative PCR analyses in the hypothalamus and brain stem revealed that the 20:80 whey:casein milk intake upregulated genes involved in early termination of feeding and in an interplay between reward and satiety, such as melanocortin 3 receptor (MC3R), oxytocin (OXT), proopiomelanocortin (POMC) and glucagon-like peptide-1 receptor (GLP1R). The 20:80 versus 60:40 whey:casein formulation intake differently affected brain neuronal activation (assessed through c-Fos, an immediate-early gene product) in the nucleus of the solitary tract, area postrema, ventromedial hypothalamic nucleus and supraoptic nucleus. We conclude that the shift from the 20:80 to 60:40 whey:casein ratio in milk affects short-term feeding and relevant brain processes.

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Developmental up-regulation of NMDA receptors in the prefrontal cortex and hippocampus of mGlu5 receptor knock-out mice

Molecular Brain ◽

10.1186/s13041-021-00784-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tiziana Imbriglio ◽

Remy Verhaeghe ◽

Nico Antenucci ◽

Stefania Maccari ◽

Giuseppe Battaglia ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nmda Receptor ◽

Metabotropic Glutamate Receptors ◽

Adult Life ◽

Developmental Time ◽

Postnatal Life ◽

Developmental Studies ◽

Knock Out ◽

Nmda Receptor Subunits ◽

The Impact

AbstractmGlu5 metabotropic glutamate receptors are highly expressed and functional in the early postnatal life, and are known to positively modulate NMDA receptor function. Here, we examined the expression of NMDA receptor subunits and interneuron-related genes in the prefrontal cortex and hippocampus of mGlu5−/− mice and wild-type littermates at three developmental time points (PND9, − 21, and − 75). We were surprised to find that expression of all NMDA receptor subunits was greatly enhanced in mGlu5−/− mice at PND21. In contrast, at PND9, expression of the GluN2B subunit was enhanced, whereas expression of GluN2A and GluN2D subunits was reduced in both regions. These modifications were transient and disappeared in the adult life (PND75). Changes in the transcripts of interneuron-related genes (encoding parvalbumin, somatostatin, vasoactive intestinal peptide, reelin, and the two isoforms of glutamate decarboxylase) were also observed in mGlu5−/− mice across postnatal development. For example, the transcript encoding parvalbumin was up-regulated in the prefrontal cortex of mGlu5−/− mice at PND9 and PND21, whereas it was significantly reduced at PND75. These findings suggest that in mGlu5−/− mice a transient overexpression of NMDA receptor subunits may compensate for the lack of the NMDA receptor partner, mGlu5. Interestingly, in mGlu5−/− mice the behavioral response to the NMDA channel blocker, MK-801, was significantly increased at PND21, and largely reduced at PND75. The impact of adaptive changes in the expression of NMDA receptor subunits should be taken into account when mGlu5−/− mice are used for developmental studies.

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