scholarly journals Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1

2021 ◽  
Author(s):  
Pablo J. Lituma ◽  
Evan Woo ◽  
Bruce F. O’Hara ◽  
Pablo E. Castillo ◽  
Nicholas E. S. Sibinga ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neurodegenerative Disorders ◽  
Brain Function ◽  
Hippocampal Slices ◽  
Autism Spectrum ◽  
Excitatory Synapse ◽  
Adapter Protein ◽  
Acute Hippocampal Slices ◽  
And Behavior ◽  
Synaptic Pruning

AbstractGrowing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation, as well as synaptic transmission and plasticity. Iba1 (Ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global Iba1-deficient (Aif1-/-) mice to characterize microglial activity, synaptic function and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1-/- microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1-/- brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1-/- mice displayed deficits in excitatory synapse number and synaptic transmission assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1-/- mice. During early postnatal development when synapse formation is a predominant event in the hippocampus, excitatory synapse number was still reduced in Aif1-/- mice. Together these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in the adulthood and correlated with significant behavioral changes in adult Aif1-/- mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuro-glia developmental processes that may deeply influence behavior.SignificanceAbnormal microglia-neuron interaction is increasingly implicated in neurodevelopmental and neuropsychiatric conditions such as autism spectrum disorders and schizophrenia, as well as in neurodegenerative disorders such as Alzheimer’s disease. This study demonstrates that deletion of the microglia-specific protein Iba1, which has long been utilized as a selective microglial marker but whose role has remained unidentified, results in microglial structural and functional impairments that significantly impact synaptic development and behavior. These findings not only highlight the importance of microglia in brain function but may also suggest that modifying microglial function could provide a therapeutic strategy for treatment of neurodevelopmental, neuropsychiatric and neurodegenerative disorders.

scholarly journals Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1

2021 ◽  
Vol 118 (46) ◽  
pp. e2115539118
Author(s):  
Pablo J. Lituma ◽  
Evan Woo ◽  
Bruce F. O’Hara ◽  
Pablo E. Castillo ◽  
Nicholas E. S. Sibinga ◽  
...  
Keyword(s):  
Brain Function ◽  
Hippocampal Slices ◽  
Synaptic Function ◽  
Excitatory Synapse ◽  
Inflammatory Factor ◽  
Adapter Protein ◽  
Patch Clamp Recording ◽  
Cellular Marker ◽  
Acute Hippocampal Slices ◽  
Synaptic Pruning

Growing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation as well as synaptic transmission and plasticity. Iba1 (ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global, Iba1-deficient (Aif1−/−) mice to characterize microglial activity, synaptic function, and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1−/− microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1−/− brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1−/− mice displayed deficits in the excitatory synapse number and synaptic drive assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1−/− mice. During early postnatal development, when synapse formation is a predominant event in the hippocampus, the excitatory synapse number was still reduced in Aif1−/− mice. Together, these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in adulthood and correlated with significant behavioral changes in adult Aif1−/− mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuroglia developmental processes that may deeply influence behavior.

scholarly journals Adenosine A1 receptor-mediated protection of mouse hippocampal synaptic transmission against oxygen and/or glucose deprivation: a comparative study

2019 ◽  
Vol 122 (2) ◽  
pp. 721-728 ◽  
Author(s):  
Masahito Kawamura ◽  
David N. Ruskin ◽  
Susan A. Masino
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Acute Response ◽  
Recording Conditions ◽  
Receptor Inactivation ◽  
Acute Hippocampal Slices ◽  
Metabolic Stresses ◽  
The Impact

Adenosine receptors are widely expressed in the brain, and adenosine is a key bioactive substance for neuroprotection. In this article, we clarify systematically the role of adenosine A1 receptors during a range of timescales and conditions when a significant amount of adenosine is released. Using acute hippocampal slices obtained from mice that were wild type or null mutant for the adenosine A1 receptor, we quantified and characterized the impact of varying durations of experimental ischemia, hypoxia, and hypoglycemia on synaptic transmission in the CA1 subregion. In normal tissue, these three stressors rapidly and markedly reduced synaptic transmission, and only treatment of sufficient duration led to incomplete recovery. In contrast, inactivation of adenosine A1 receptors delayed and/or lessened the reduction in synaptic transmission during all three stressors and reduced the magnitude of the recovery significantly. We reproduced the responses to hypoxia and hypoglycemia by applying an adenosine A1 receptor antagonist, validating the clear effects of genetic receptor inactivation on synaptic transmission. We found activation of adenosine A1 receptor inhibited hippocampal synaptic transmission during the acute phase of ischemia, hypoxia, or hypoglycemia and caused the recovery from synaptic impairment after these three stressors using genetic mutant. These studies quantify the neuroprotective role of the adenosine A1 receptor during a variety of metabolic stresses within the same recording system. NEW & NOTEWORTHY Deprivation of oxygen and/or glucose causes a rapid adenosine A1 receptor-mediated decrease in synaptic transmission in mouse hippocampus. We quantified adenosine A1 receptor-mediated inhibition during and synaptic recovery after ischemia, hypoxia, and hypoglycemia of varying durations using a genetic mutant and confirmed these findings using pharmacology. Overall, using the same recording conditions, we found the acute response and the neuroprotective ability of the adenosine A1 receptor depended on the type and duration of deprivation event.

scholarly journals Parvalbumin expression and gamma oscillation occurrence increase over time in a neurodevelopmental model of NMDA receptor dysfunction

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5543
Author(s):  
Ben van Lier ◽  
Andreas Hierlemann ◽  
Frédéric Knoflach
Keyword(s):  
Synaptic Transmission ◽  
Peak Power ◽  
Hippocampal Slices ◽  
Gamma Oscillations ◽  
Peak Frequency ◽  
Oscillatory Activity ◽  
Therapeutic Drugs ◽  
Acute Hippocampal Slices ◽  
Over Time

Dysfunction of the N-methyl-d-aspartate receptor (NMDAR) is thought to play a role in the pathophysiology of neurodevelopmental diseases like schizophrenia. To study the effects of NMDAR dysfunction on synaptic transmission and network oscillations, we used hippocampal tissue of NMDAR subunit GluN2A knockout (KO) mice. Field excitatory postsynaptic potentials were recorded in acute hippocampal slices of adult animals. Synaptic transmission was impaired in GluN2A KO slices compared to wild-type (WT) slices. Further, to investigate whether NMDAR dysfunction would alter neurodevelopment in vitro, we used organotypic hippocampal slice cultures of WT and GluN2A KO mice. Immunostaining performed with cultures kept two, seven, 14, 25 days in vitro (DIV) revealed an increasing expression of parvalbumin (PV) over time. As a functional readout, oscillatory activity induced by the cholinergic agonist carbachol was recorded in cultures kept seven, 13, and 26 DIV using microelectrode arrays. Initial analysis focused on the occurrence of delta, theta, beta and gamma oscillations over genotype, DIV and hippocampal area (CA1, CA3, dentate gyrus (DG)). In a follow-up analysis, we studied the peak frequency and the peak power of each of the four oscillation bands per condition. The occurrence of gamma oscillations displayed an increase by DIV similar to the PV immunostaining. Unlike gamma occurrence, delta, theta, and beta occurrence did not change over time in culture. The peak frequency and peak power in the different bands of the oscillations were not different in slices of WT and GluN2A KO mice. However, the level of PV expression was lower in GluN2A KO compared to WT mice. Given the role of PV-containing fast-spiking basket cells in generation of oscillations and the decreased PV expression in subjects with schizophrenia, the study of gamma oscillations in organotypic hippocampal slices represents a potentially valuable tool for the characterization of novel therapeutic drugs.

scholarly journals Alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior

2019 ◽  
Author(s):  
Renato Socodato ◽  
Joana F. Henriques ◽  
Camila C. Portugal ◽  
Tiago O. Almeida ◽  
Joana Tedim-Moreira ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Synaptic Transmission ◽  
Alcohol Intake ◽  
Alcohol Intoxication ◽  
Excitatory Synapse ◽  
Genetic Ablation ◽  
Synapse Loss ◽  
Pharmacological Blockade ◽  
Alcohol Users ◽  
Synaptic Pruning

AbstractAlcohol use adversely impacts the life of millions of people worldwide. Deficits in synaptic transmission and in microglial function are common findings in human alcohol users and in animal models of alcohol intoxication. Here, we show that alcohol intake over ten consecutive days resulted in substantial loss of excitatory synapse in the prefrontal cortex, a consequence of aberrant synaptic pruning, which led to increased anxiety-like behavior. Mechanistically, these effects of alcohol intake were mediated by a detrimental increase of microglia engulfment capacity via Src-dependent activation of NFkB and consequent TNF production. Accordingly, pharmacological blockade of Src activation or TNF production by microglia, genetic ablation of TNF, or diphtheria toxin-mediated conditional ablation of microglia attenuated aberrant synaptic pruning preventing excitatory synapse loss and anxiety-like behavior. Overall, our data suggest that aberrant pruning of excitatory synapses by microglia might disrupt synaptic transmission during alcohol use.

scholarly journals Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

2022 ◽  
Author(s):  
Anika Heinze ◽  
Cara Schuldt ◽  
Sharof Khudayberdiev ◽  
Bas van Bommel ◽  
Daniela Hacker ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Dendritic Spines ◽  
Brain Function ◽  
Hippocampal Neurons ◽  
Super Resolution ◽  
Actin Binding ◽  
Spine Morphology ◽  
Actin Organization ◽  
Major Structural Component ◽  
And Behavior

Abstract The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are both crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Because actin filaments (F-actin) are the major structural component in spines, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Indeed, mouse studies identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission and behavior. These studies emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. We report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperated with cofilin1 in spines and that its helical folded domain mediated this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that was essential for synaptic cofilin1 activity.

scholarly journals Carbachol-Induced Long-Term Synaptic Depression Is Enhanced During Senescence at Hippocampal CA3–CA1 Synapses

2010 ◽  
Vol 104 (2) ◽  
pp. 607-616 ◽  
Author(s):  
Ashok Kumar
Keyword(s):  
Synaptic Transmission ◽  
Memory Performance ◽  
Hippocampal Slices ◽  
Age Groups ◽  
Cholinergic Receptor ◽  
Fischer 344 ◽  
Bath Application ◽  
Hippocampal Ca3 ◽  
Acute Hippocampal Slices

Dysregulation of the cholinergic transmitter system is a hallmark of Alzheimer's disease and contributes to an age-associated decline in memory performance. The current study examined the influence of carbachol, a cholinergic receptor agonist, on synaptic transmission over the course of aging. Extracellular excitatory postsynaptic field potentials were recorded from CA3–CA1 synapses in acute hippocampal slices obtained from young adult (5–8 mo) and aged (22–24 mo) male Fischer 344 rats. Bath application of carbachol elicited a transient depression of synaptic transmission, which was followed by a long-lasting depression (CCh-LTD) observed 90 min after carbachol cessation in both age groups. However, the magnitude of CCh-LTD was significantly larger in senescent animals and was attenuated by N-methyl-d-aspartate receptor blockade in aged animals. Blockade of L-type Ca2+ channels inhibited CCh-LTD to a greater extent in aged animals compared to young adults. Finally, the expression of CCh-LTD was dependent on protein synthesis. The results indicate that altered Ca2+ homeostasis or muscarinic activation of Ca2+ signaling contribute to the enhanced CCh-LTD during senescence.

scholarly journals Activity-Dependent Plasticity of Astroglial Potassium and Glutamate Clearance

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Giselle Cheung ◽  
Jérémie Sibille ◽  
Jonathan Zapata ◽  
Nathalie Rouach
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Activity ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Extracellular Potassium ◽  
Inward Currents ◽  
Frequency Stimulation ◽  
Short And Long Term ◽  
Acute Hippocampal Slices

Recent evidence has shown that astrocytes play essential roles in synaptic transmission and plasticity. Nevertheless, how neuronal activity alters astroglial functional properties and whether such properties also display specific forms of plasticity still remain elusive. Here, we review research findings supporting this aspect of astrocytes, focusing on their roles in the clearance of extracellular potassium and glutamate, two neuroactive substances promptly released during excitatory synaptic transmission. Their subsequent removal, which is primarily carried out by glial potassium channels and glutamate transporters, is essential for proper functioning of the brain. Similar to neurons, different forms of short- and long-term plasticity in astroglial uptake have been reported. In addition, we also present novel findings showing robust potentiation of astrocytic inward currents in response to repetitive stimulations at mild frequencies, as low as 0.75 Hz, in acute hippocampal slices. Interestingly, neurotransmission was hardly affected at this frequency range, suggesting that astrocytes may be more sensitive to low frequency stimulation and may exhibit stronger plasticity than neurons to prevent hyperexcitability. Taken together, these important findings strongly indicate that astrocytes display both short- and long-term plasticity in their clearance of excess neuroactive substances from the extracellular space, thereby regulating neuronal activity and brain homeostasis.

Homeostatic plasticity induced by brief activity deprivation enhances long-term potentiation in the mature rat hippocampus

2014 ◽  
Vol 112 (11) ◽  
pp. 3012-3022 ◽  
Author(s):  
A. Félix-Oliveira ◽  
R. B. Dias ◽  
M. Colino-Oliveira ◽  
D. M. Rombo ◽  
A. M. Sebastião
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Relative Strength ◽  
Homeostatic Plasticity ◽  
Hebbian Plasticity ◽  
Term Potentiation ◽  
Acute Hippocampal Slices

Different forms of plasticity occur concomitantly in the nervous system. Whereas homeostatic plasticity monitors and maintains neuronal activity within a functional range, Hebbian changes such as long-term potentiation (LTP) modify the relative strength of specific synapses after discrete changes in activity and are thought to provide the cellular basis for learning and memory. Here, we assessed whether homeostatic plasticity could influence subsequent LTP in acute hippocampal slices that had been briefly deprived of activity by blocking action potential generation and N-methyl-d-aspartate (NMDA) receptor activation for 3 h. Activity deprivation enhanced the frequency and the amplitude of spontaneous miniature excitatory postsynaptic currents and enhanced basal synaptic transmission in the absence of significant changes in intrinsic excitability. Changes in the threshold for Hebbian plasticity were evaluated by inducing LTP with stimulation protocols of increasing strength. We found that activity-deprived slices consistently showed higher LTP magnitude compared with control conditions even when using subthreshold theta-burst stimulation. Enhanced LTP in activity-deprived slices was also observed when picrotoxin was used to prevent the modulation of GABAergic transmission. Finally, we observed that consecutive LTP inductions attained a higher magnitude of facilitation in activity-deprived slices, suggesting that the homeostatic plasticity mechanisms triggered by a brief period of neuronal silencing can both lower the threshold and raise the ceiling for Hebbian modifications. We conclude that even brief periods of altered activity are able to shape subsequent synaptic transmission and Hebbian plasticity in fully developed hippocampal circuits.

Cell adhesion proteins and the pathogenesis of autism spectrum disorders

2015 ◽  
Vol 113 (5) ◽  
pp. 1283-1286 ◽  
Author(s):  
Luke T. Stewart
Keyword(s):  
Autism Spectrum Disorders ◽  
Cell Adhesion ◽  
Hippocampal Slices ◽  
Autism Spectrum ◽  
Adhesion Proteins ◽  
Brain Circuits ◽  
Alternatively Spliced ◽  
Spectrum Disorders ◽  
Acute Hippocampal Slices ◽  
Cell Adhesion Proteins

Current theories on the pathogenesis of autism spectrum disorders (ASD) maintain that the associated cognitive and behavioral symptoms are caused by aberrant synaptic transmission affecting specific brain circuits. Transgenic mouse models have implicated the involvement of cell adhesion proteins in synaptic dysfunction and ASD pathogenesis. Recently, Aoto et al. ( Cell 154: 75–88, 2013) has shown that alternatively spliced neurexin proteins affect the efficacy of AMPA receptor-mediated excitatory currents in both cultured neuronal networks and acute hippocampal slices constituting a potential ASD-related electrophysiological phenotype.

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