scholarly journals Gabaergic Interneurons in Early Brain Development: Conducting and Orchestrated by Cortical Network Activity

2022 ◽  
Vol 14 ◽  
Author(s):  
Davide Warm ◽  
Jonas Schroer ◽  
Anne Sinning
Keyword(s):  
Brain Development ◽  
Specific Activity ◽  
Activity Patterns ◽  
Gamma Oscillations ◽  
Cortical Network ◽  
Neuronal Firing ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Sensory Evoked ◽  
And Function

Throughout early phases of brain development, the two main neural signaling mechanisms—excitation and inhibition—are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced—if not directly controlled—by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns—as well as how specific activity patterns impinge on their maturation as orchestra members—will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system.

scholarly journals Altered GABAA,slow Inhibition and Network Oscillations in Mice Lacking the GABAA Receptor β3 Subunit

2009 ◽  
Vol 102 (6) ◽  
pp. 3643-3655 ◽  
Author(s):  
Harald Hentschke ◽  
Claudia Benkwitz ◽  
Matthew I. Banks ◽  
Mark G. Perkins ◽  
Gregg E. Homanics ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Gamma Oscillations ◽  
Theta Oscillations ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Gabaergic Inhibition ◽  
Wild Type ◽  
Hippocampal Network

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABAA,fast and GABAA,slow. In hippocampal area CA1, GABAA,fast is generally believed to underlie gamma oscillations, whereas the contribution of GABAA,slow to hippocampal rhythms has been speculative. Hypothesizing that GABAA receptors containing the β3 subunit contribute to GABAA,slow inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABAA receptor β3 subunit-deficient (β3−/−) mice, spontaneous GABAA,slow inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABAA,slow currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing β3 subunits contribute substantially to GABAA,slow currents in pyramidal neurons. By contrast, slow inhibitory control of GABAA,fast-producing interneurons was unaffected in β3−/− mice. In vivo hippocampal network activity was markedly different in the two genotypes. In β3−/− mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency (“nesting”) was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of β3 subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABAA,fast -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

scholarly journals Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation

2014 ◽  
Vol 112 (1) ◽  
pp. E65-E72 ◽  
Author(s):  
Carmen E. Flores ◽  
Irina Nikonenko ◽  
Pablo Mendez ◽  
Jean-Marc Fritschy ◽  
Shiva K. Tyagarajan ◽  
...  
Keyword(s):  
Activity Patterns ◽  
Phosphorylation Site ◽  
Morphological Plasticity ◽  
Long Term Potentiation ◽  
Inhibitory Synapse ◽  
Inhibitory Synapses ◽  
Synapse Plasticity ◽  
Inhibitory Plasticity ◽  
And Function ◽  
Activity Dependent

Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca2+/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.

scholarly journals Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis

2017 ◽  
Vol 24 (2) ◽  
pp. 130-141 ◽  
Author(s):  
Nailya Lotfullina ◽  
Roustem Khazipov
Keyword(s):  
Nmda Receptors ◽  
Neuronal Activity ◽  
Activity Patterns ◽  
Gamma Oscillations ◽  
Cortical Activity ◽  
Neuronal Firing ◽  
Developing Brain ◽  
Pathophysiological Mechanism ◽  
Intracortical Circuits ◽  
Early Activity

Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d-aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain.

scholarly journals Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output

2019 ◽  
Author(s):  
Matt Udakis ◽  
Victor Pedrosa ◽  
Sophie E.L. Chamberlain ◽  
Claudia Clopath ◽  
Jack R Mellor
Keyword(s):  
Pyramidal Neurons ◽  
Physiological Activity ◽  
Activity Patterns ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Cell ◽  
Hippocampal Network

SummaryThe formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.

scholarly journals Essential role for InSyn1 in dystroglycan complex integrity and cognitive behaviors in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Akiyoshi Uezu ◽  
Erin Hisey ◽  
Yoshihiko Kobayashi ◽  
Yudong Gao ◽  
Tyler WA Bradshaw ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Neuronal Firing ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Synaptic Organization ◽  
Cognitive Behaviors ◽  
Neuronal Network Activity

Human mutations in the dystroglycan complex (DGC) result in not only muscular dystrophy but also cognitive impairments. However, the molecular architecture critical for the synaptic organization of the DGC in neurons remains elusive. Here, we report Inhibitory Synaptic protein 1 (InSyn1) is a critical component of the DGC whose loss alters the composition of the GABAergic synapses, excitatory/inhibitory balance in vitro and in vivo, and cognitive behavior. Association of InSyn1 with DGC subunits is required for InSyn1 synaptic localization. InSyn1 null neurons also show a significant reduction in DGC and GABA receptor distribution as well as abnormal neuronal network activity. Moreover, InSyn1 null mice exhibit elevated neuronal firing patterns in the hippocampus and deficits in fear conditioning memory. Our results support the dysregulation of the DGC at inhibitory synapses and altered neuronal network activity and specific cognitive tasks via loss of a novel component, InSyn1.

scholarly journals Test-retest reliability of tone- and 40 Hz train-evoked gamma oscillations in female rats and their sensitivity to low-dose NMDA channel blockade

2021 ◽  
Author(s):  
Muhammad Ummear Raza ◽  
Digavalli V. Sivarao
Keyword(s):  
Gamma Oscillations ◽  
Female Rats ◽  
Network Activity ◽  
Multiple Time ◽  
Evoked Responses ◽  
Retest Reliability ◽  
Sensory Evoked ◽  
Test Retest Reliability ◽  
40 Hz

Rationale: Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40 Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical development of drug candidates engaging these circuits. However, there is little test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms. Objectives: We investigated the long-term stability of these measures in a rodent model. Methods: Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025-0.15 mg/kg) to disrupt the evoked responses. Results: We found that 40 Hz ASSR showed good reliability (ICC=0.60-0.75) while the reliability of tone-evoked gamma ranged from poor to good (0.33-0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism. Conclusion: Overall, while both measures use NMDA transmission, 40 Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.

scholarly journals Disparate energy consumption despite similar network activity

2021 ◽  
Author(s):  
Michael Deistler ◽  
Jakob H Macke ◽  
Pedro J Goncalves
Keyword(s):  
Energy Consumption ◽  
Neural Circuits ◽  
Specific Activity ◽  
Activity Patterns ◽  
Network Models ◽  
Metabolic Cost ◽  
Network Activity ◽  
Metabolic Efficiency ◽  
Cancer Borealis ◽  
Similar Activity

Neural circuits can produce similar activity patterns from vastly different combinations of channel and synaptic conductances. These conductances are tuned for specific activity patterns but might also reflect additional constraints, such as metabolic cost or robustness to perturbations. How do such constraints influence the range of permissible conductances? Here, we investigate how metabolic cost affects the parameters of neural circuits with similar activity in a model of the pyloric network of the crab Cancer borealis. We use a novel machine learning method to identify a range of network models that can generate activity patterns matching experimental data. We find that neural circuits can consume largely different amounts of energy despite similar circuit activity. We then study how circuit parameters get constrained by minimizing energy consumption and identify circuit parameters that might be subject to metabolic tuning. Finally, we investigate the interaction between metabolic cost and temperature robustness. We show that metabolic cost can vary across temperatures, but that robustness to temperature changes does not necessarily incur an increased metabolic cost. Our analyses show that, despite metabolic efficiency and temperature robustness constraining circuit parameters, neural systems can generate functional, efficient, and robust network activity with widely disparate sets of conductances.

scholarly journals Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

2020 ◽  
Author(s):  
Galina Schmunk ◽  
Chang N. Kim ◽  
Sarah S. Soliman ◽  
Matthew G. Keefe ◽  
Derek Bogdanoff ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Functional Characterization ◽  
Experimental Models ◽  
Vital Role ◽  
Network Activity ◽  
Human Microglia ◽  
Human Brain Development ◽  
Culture Models ◽  
And Function

AbstractMicroglia are the resident macrophages of the brain that emerge in early development and play vital role disease states, as well as in normal development. Many fundamental questions about microglia diversity and function during human brain development remain unanswered, as we currently lack cellular-resolution datasets focusing on microglia in developing primary tissue, or experimental strategies for interrogating their function. Here, we report an integrative analysis of microglia throughout human brain development, which reveals molecular signatures of stepwise maturation, as well as human-specific cytokine-associated subtype that emerges around the onset of neurogenesis. To demonstrate the utility of this atlas, we have compared microglia across several culture models, including cultured primary microglia, pluripotent stem cell-derived microglia. We identify gene expression signatures differentially recruited and attenuated across experimental models, which will accelerate functional characterization of microglia across perturbations, species, and disease conditions. Finally, we identify a role for human microglia in development of synchronized network activity using a xenotransplantation model of human microglia into cerebral organoids.

Predicting spatial activity patterns in a neural map from a probabilistic atlas of 3-D reconstructed neurons

1995 ◽  
Vol 53 ◽  
pp. 812-813
Author(s):  
G. Jacobs ◽  
F. Theunissen
Keyword(s):  
Activity Patterns ◽  
Three Dimensional ◽  
Sensory System ◽  
Neural System ◽  
Probabilistic Atlas ◽  
Uniform Sample ◽  
Dimensional Reconstruction ◽  
The Time Domain ◽  
And Function ◽  
Visualization Techniques

In order to understand how the algorithms underlying neural computation are implemented within any neural system, it is necessary to understand details of the anatomy, physiology and global organization of the neurons from which the system is constructed. Information is represented in neural systems by patterns of activity that vary in both their spatial extent and in the time domain. One of the great challenges to microscopists is to devise methods for imaging these patterns of activity and to correlate them with the underlying neuroanatomy and physiology. We have addressed this problem by using a combination of three dimensional reconstruction techniques, quantitative analysis and computer visualization techniques to build a probabilistic atlas of a neural map in an insect sensory system. The principal goal of this study was to derive a quantitative representation of the map, based on a uniform sample of afferents that was of sufficient size to allow statistically meaningful analyses of the relationships between structure and function.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

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