Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model.
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ABSTRACT:
SUBMITTER: Xia D
PROVIDER: S-EPMC8072465 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neural circuits and behavior are shaped during developmental phases of maximal plasticity known as sensitive or critical periods. Neural correlates of sensory critical periods have been identified, but their roles remain unclear. Factors that define critical periods in sensorimotor circuits and behavior are not known. Birdsong learning in the zebra finch occurs during a sensitive period similar to that for human speech. We now show that perineuronal nets, which correlate with sensory critical periods, surround parvalbumin-positive neurons in brain areas that are dedicated to singing. The percentage of both total and parvalbumin-positive neurons with perineuronal nets increased with development. In HVC (this acronym is the proper name), a song area important for sensorimotor integration, the percentage of parvalbumin neurons with perineuronal nets correlated with song maturity. Shifting the vocal critical period with tutor song deprivation decreased the percentage of neurons that were parvalbumin positive and the relative staining intensity of both parvalbumin and a component of perineuronal nets. Developmental song learning shares key characteristics with sensory critical periods, suggesting shared underlying mechanisms.
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Project description:Perineuronal nets (PNNs), a complex of extracellular matrix molecules that mostly surround GABAergic neurons in various brain regions, play a critical role in synaptic plasticity. The function and cellular mechanisms of PNNs in memory consolidation and reconsolidation processes are still not well understood. We hypothesized that PNNs protect long-term memory by limiting feedback inhibition from parvalbumin (PV) interneurons to projection neurons. Using behavioral, electrophysiological, and optogenetic approaches, we investigated the role of PNNs in fear memory consolidation and reconsolidation and GABAergic long-term potentiation (LTP). We made the discovery that the formation of PNNs was promoted by memory events in the hippocampus (HP), and we also demonstrated that PNN formation in both the HP and the anterior cingulate cortex (ACC) is essential for memory consolidation and reconsolidation of recent and remote memories. Removal of PNNs resulted in evident LTP impairments, which were rescued by acute application of picrotoxin, a GABAA receptor blocker, indicating that enhanced inhibition was the cause of the LTP impairments induced by PNN removal. Moreover, removal of PNNs switched GABAA receptor-mediated long-term depression to LTP through a presynaptic mechanism. Furthermore, the reduced activity of PV interneurons surrounded by PNNs regulated theta oscillations during fear memory consolidation. Finally, optogenetically suppressing PV interneurons rescued the memory impairment caused by removal of PNNs. Altogether, these results unveil the function of PV interneurons surrounding PNNs in protecting recent and remote contextual memory through the regulation of PV neuron GABA release.
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Project description:Adult-born granule cells (abGCs) integrate into the hippocampus and form connections with dentate gyrus parvalbumin-positive (PV+) interneurons, a circuit important for modulating plasticity. Many of these interneurons are surrounded by perineuronal nets (PNNs), extracellular matrix structures known to participate in plasticity. We compared abGC projections to PV+ interneurons with negative-to-low intensity PNNs to those with high intensity PNNs using retroviral and 3R-Tau labeling in adult mice, and found that abGC mossy fibers and boutons are more frequently located near PV+ interneurons with high intensity PNNs. These results suggest that axons of new neurons preferentially stabilize near target cells with intense PNNs. Next, we asked whether the number of abGCs influences PNN formation around PV+ interneurons, and found that near complete ablation of abGCs produced a decrease in the intensity and number of PV+ neurons with PNNs, suggesting that new neuron innervation may enhance PNN formation. Experience-driven changes in adult neurogenesis did not produce consistent effects, perhaps due to widespread effects on plasticity. Our study identifies abGC projections to PV+ interneurons with PNNs, with more presumed abGC mossy fiber boutons found near the cell body of PV+ interneurons with strong PNNs.
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Project description:Alterations in cortical parvalbumin (PV)-containing neurons, including a reduced density of detectable neurons and lower PV levels, have frequently been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects. Most PV neurons are surrounded by perineuronal nets (PNNs) and the density of PNNs, as detected by Wisteria floribunda agglutinin (WFA) labeling, has been reported to be lower in schizophrenia. However, the nature of these PNN alterations, and their relationship to disease-related changes in PV neurons, has not been assessed. Using confocal microscopy, we quantified the densities and fluorescence intensities of PV neurons and PNNs labeled with WFA or immunoreactive for the major PNN protein, aggrecan, in the DLPFC from schizophrenia and matched comparison subjects. In schizophrenia, the densities of PV cells and of PNNs were not altered; however, the fluorescence intensities of PV immunoreactivity in cell bodies and of WFA labeling and aggrecan immunoreactivity in individual PNNs around PV cells were lower. These findings indicate that the normal complements of PV cells and PNNs are preserved in schizophrenia, but the levels of PV protein and of individual PNN components, especially the carbohydrate moieties on proteoglycans to which WFA binds, are lower. Given the roles of PV neurons in regulating DLPFC microcircuits and of PNNs in regulating PV cellular physiology, the identified alterations in PV neurons and their PNNs could contribute to DLPFC dysfunction in schizophrenia.
| S-EPMC4946056 | biostudies-literature
Project description:Early life adversity impacts on a range of emotional, cognitive, and psychological processes. A recent theoretical model suggests that at least some of these effects are due to accelerated maturation of specific physiological systems and/or neural circuits. For example, maternal separation (MS), a model of early life adversity in rodents, accelerates maturation of memory systems, and here we examined its impact on maturation of perineuronal nets (PNNs) and parvalbumin (PV)-containing inhibitory interneurons. PNNs are specialized extracellular matrix structures suggested to be involved in stabilizing long-term memories and in the closure of a sensitive period in memory development. PV-containing inhibitory interneurons are the type of cell that PNNs preferentially surround, and are also thought to be involved in memory. In Experiment 1, with male rats, there was an increase in PNNs in both the amygdala and prefrontal cortex with age from infancy to juvenility. Contrary to prediction, MS had no impact on either PNN or PV expression. The same pattern was observed in female rats in Experiment 2. Taken together, these data show that the early maturation of memory in MS infants is not due to an accelerated maturation of PNNs or PV-containing cells in either the amygdala or prefrontal cortex.
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Project description:BACKGROUND: The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders, but cellular mechanisms underlying the antidepressant effect of FLX remain largely unknown. The generally accepted effect of chronic FLX treatment is increased adult neurogenesis in the hippocampal dentate gyrus. It was recently demonstrated that FLX treatments can reverse the established neuronal maturation of granule cells in the hippocampal dentate gyrus and of gamma-aminobutyric acidergic (GABAergic) interneurons in the basolateral amygdala. However, it is not clear whether this dematuration effect of FLX occurs in other brain regions. Thus, in this study, we used immunohistological analysis to assess the effect of FLX treatment on GABAergic interneurons in the medial frontal cortex (mFC) and reticular thalamic nucleus (RTN). RESULTS: Immunofluorescence analysis for perineuronal nets (PNNs), which is a marker of neuronal maturation, and for parvalbumin, calretinin, and somatostatin, which are markers for specific GABAergic interneuron type, showed lower number of parvalbumin-positive (+) cells and PNN+/parvalbumin+?cells in the mFC of FLX-treated mice compared to vehicle-treated mice. However, FLX treatment had no effect on the number of cells expressing calretinin and somatostatin in the mFC. In the RTN, the number of PNN+?cells and parvalbumin+?cells was unaltered by FLX treatments. Furthermore, the number of total GABA+?cells and apoptotic cells in the mFC was similar between vehicle- and FLX-treated mice, suggesting that FLX treatment did not induce cell death in this region. Rather, our findings suggest that the decreased number of parvalbumin+?cells in the mFC was due to a decreased expression of parvalbumin proteins in the interneurons. CONCLUSIONS: This study indicates that FLX decreases the levels of parvalbumin, a mature marker of fast-spiking interneurons, and PNNs in parvalbumin+ interneurons in the mFC, suggesting that FLX treatment induces a dematuration of this type of neurons. Induction of a juvenile-like state in fast-spiking inhibitory interneurons in these regions might be involved in the therapeutic mechanism of this antidepressant drug and/or some of its adverse effects.
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Project description:Aberrant processing of auditory stimuli is a prominent feature of schizophrenia (SZ). Prior studies have chronicled histological abnormalities in the auditory cortex of SZ subjects, but whether deficits exist at upstream, subcortical levels has yet to be established. En route to the auditory cortex, ascending information is integrated in the inferior colliculus (IC), a highly gamma amino butyric acid (GABA) ergic midbrain structure that is critically involved in auditory processing. The IC contains a dense population of parvalbumin-immunoreactive interneurons (PVIs), a cell type characterized by increased metabolic demands and enhanced vulnerability to oxidative stress. During development, PVIs are preferentially surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures that promote redox homeostasis and excitatory/inhibitory balance. Moreover, in SZ, deficits in PVIs, PNNs, and the GABA synthesizing enzyme, glutamic acid decarboxylase (Gad67), have been extensively documented in cortical regions. Yet, whether similar impairments exist in the IC is currently unknown. Thus, we compared IC samples of age- and sex-matched pairs of SZ and unaffected control subjects. SZ subjects exhibited lower levels of Gad67 immunoreactivity and a decreased density of PVIs and PNNs within the IC. These findings provide the first histological evidence of IC GABAergic abnormalities in SZ and suggest that SZ-related auditory dysfunction may stem, in part, from altered IC inhibitory tone.
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Project description:The perineuronal net (PNN) region of the brain's extracellular matrix (ECM) surrounds the neural networks within the brain tissue. The PNN is a protective net-like structure regulating neuronal activity such as neurotransmission, charge balance, and action potential generation. Shock-induced damage of this essential component may lead to neuronal cell death and neurodegenerations. The shock generated during a vehicle accident, fall, or improvised device explosion may produce sufficient energy to damage the structure of the PNN. The goal is to investigate the mechanics of the PNN in reaction to shock loading and to understand the mechanical properties of different PNN components such as glycan, GAG, and protein. In this study, we evaluated the mechanical strength of PNN molecules and the interfacial strength between the PNN components. Afterward, we assessed the PNN molecules' damage efficiency under various conditions such as shock speed, preexisting bubble, and boundary conditions. The secondary structure altercation of the protein molecules of the PNN was analyzed to evaluate damage intensity under varying shock speeds. At a higher shock speed, damage intensity is more elevated, and hyaluronan (glycan molecule) is most likely to break at the rigid junction. The primary structure of the protein molecules is least likely to fail. Instead, the molecules' secondary bonds will be altered. Our study suggests that the number of hydrogen bonds during the shock wave propagation is reduced, which leads to the change in protein conformations and damage within the PNN structure. As such, we found a direct connection between shock wave intensity and PNN damage.
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Project description:Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells' ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.
| S-EPMC7801665 | biostudies-literature
Project description:A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.
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