scholarly journals Cell-autonomous role of Presenilin in age-dependent survival of cortical interneurons

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jongkyun Kang ◽  
Jie Shen
Keyword(s):  
Cerebral Cortex ◽  
Inhibitory Neuron ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Double Knockout ◽  
Normal Number ◽  
Cortical Interneurons ◽  
Age Dependent ◽  
Excitatory Neurons

Abstract Background Mutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer’s disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored. Methods To determine PS function in GABAergic neurons, we generated inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice, in which PS is selectively inactivated by Cre recombinase expressed under the control of the endogenous GAD2 promoter. We then performed behavioral, biochemical, and histological analyses to evaluate the consequences of selective PS inactivation in inhibitory neurons. Results IN-PS cDKO mice exhibit earlier mortality and lower body weight despite normal food intake and basal activity. Western analysis of protein lysates from various brain sub-regions of IN-PS cDKO mice showed significant reduction of PS1 levels and dramatic accumulation of γ-secretase substrates. Interestingly, IN-PS cDKO mice develop age-dependent loss of GABAergic neurons, as shown by normal number of GAD67-immunoreactive interneurons in the cerebral cortex at 2–3 months of age but reduced number of cortical interneurons at 9 months. Moreover, age-dependent reduction of Parvalbumin- and Somatostatin-immunoreactive interneurons is more pronounced in the neocortex and hippocampus of IN-PS cDKO mice. Consistent with these findings, the number of apoptotic cells is elevated in the cerebral cortex of IN-PS cDKO mice, and the enhanced apoptosis is due to dramatic increases of apoptotic interneurons, whereas the number of apoptotic excitatory neurons is unaffected. Furthermore, progressive loss of interneurons in the cerebral cortex of IN-PS cDKO mice is accompanied with astrogliosis and microgliosis. Conclusion Our results together support a cell-autonomous role of PS in the survival of cortical interneurons during aging. Together with earlier studies, these findings demonstrate a universal, essential requirement of PS in the survival of both excitatory and inhibitory neurons during aging.

scholarly journals Single-cell transcriptomic analysis identifies neocortical developmental differences between human and mouse

2020 ◽  
Author(s):  
Ziheng Zhou ◽  
Shuguang Wang ◽  
Dengwei Zhang ◽  
Xiaosen Jiang ◽  
Jie Li ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Single Cell ◽  
Developmental Trajectories ◽  
Expression Patterns ◽  
Development Stage ◽  
Inhibitory Neurons ◽  
Projection Neurons ◽  
Cerebral Cortex Development ◽  
Excitatory Neurons ◽  
Human And Mouse

AbstractBackgroundThe specification and differentiation of neocortical projection neurons is a complex process under precise molecular regulation; however, little is known about the similarities and differences in cerebral cortex development between human and mouse at single-cell resolution.ResultsHere, using single-cell RNA-seq (scRNA-seq) data we explore the divergence and conservation of human and mouse cerebral cortex development using 18,446 and 7,610 neocortical cells. Systematic cross-species comparison reveals that the overall transcriptome profile in human cerebral cortex is similar to that in mouse such as cell types and their markers genes. By single-cell trajectories analysis we find human and mouse excitatory neurons have different developmental trajectories of neocortical projection neurons, ligand-receptor interactions and gene expression patterns. Further analysis reveals a refinement of neuron differentiation that occurred in human but not in mouse, suggesting that excitatory neurons in human undergo refined transcriptional states in later development stage. By contrast, for glial cells and inhibitory neurons we detected conserved developmental trajectories in human and mouse.ConclusionsTaken together, our study integrates scRNA-seq data of cerebral cortex development in human and mouse, and uncovers distinct developing models in neocortical projection neurons. The earlier activation of cognition -related genes in human may explain the differences in behavior, learning or memory abilities between the two species.

scholarly journals Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kerstin Ure ◽  
Hui Lu ◽  
Wei Wang ◽  
Aya Ito-Ishida ◽  
Zhenyu Wu ◽  
...  
Keyword(s):  
Social Skills ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Therapeutic Option ◽  
Neurodevelopmental Disorder ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Extended Lifespan ◽  
Inhibitory Signaling

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

Epileptiform activity in microcultures containing one excitatory hippocampal neuron

1991 ◽  
Vol 65 (4) ◽  
pp. 761-770 ◽  
Author(s):  
M. M. Segal
Keyword(s):  
Action Potentials ◽  
Epileptiform Activity ◽  
Inhibitory Neuron ◽  
Excitatory Neuron ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Intracellular Recordings ◽  
Voltage Fluctuations ◽  
Excitatory Neurons ◽  
Small Voltage

1. Paroxysmal depolarizing shifts (PDSs) occur during interictal epileptiform activity. Sustained depolarizations are characteristic of ictal activity, and events resembling PDSs also occur during the sustained depolarizations. To study these elements of epileptiform activity in a simpler context, I used the in vitro chronic-excitatory-block model of epilepsy of Furshpan and Potter and the microculture technique of Segal and Furshpan. 2. Intracellular recordings were made from 93 single-neuron microcultures. Forty of these solitary neurons were excitatory, their action potentials were replaced by PDS-like events or sustained depolarizations as kynurenate was removed from the perfusion solution. PDS-like events were similar to PDSs in intact cortex, mass cultures, and microcultures with more than one neuron. Small voltage fluctuations were also seen in solitary excitatory neurons in the absence of recorded action potentials. Sustained depolarizations developed in 5 of the 40 excitatory neurons. Forty-eight of the 93 solitary neurons were inhibitory, with bicuculline-sensitive hyperpolarizations after the action potential (ascribable to gamma-aminobutyric acid-A autapses). None of the solitary inhibitory neurons displayed sustained depolarizations. Five of the 93 neurons were insensitive to both kynurenate and bicuculline and were not placed in either the excitatory or the inhibitory category. 3. Both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors contributed to the PDS-like events and sustained depolarizations. Only a non-NMDA glutamate receptor component was evident for the small voltage fluctuations. 4. Intracellular recordings were also made from two-neuron microcultures, each containing one excitatory neuron and one inhibitory neuron. Sustained depolarizations developed in five microcultures, in each case only in the excitatory neuron.

scholarly journals Top-down Control of Inhibition Reshapes Neural Dynamics Giving Rise to a Diversity of Computations

2020 ◽  
Author(s):  
Zhen Chen ◽  
Krishnan Padmanabhan
Keyword(s):  
Network Dynamics ◽  
Gamma Oscillations ◽  
Sensory Systems ◽  
Pattern Separation ◽  
Inhibitory Neurons ◽  
Top Down ◽  
Brain Areas ◽  
Excitatory Neurons ◽  
Local Circuits

AbstractGrowing evidence shows that top-down projections from excitatory neurons in higher brain areas selectively synapse onto local inhibitory interneurons in sensory systems. While this connectivity is conserved across sensory modalities, the role of this feedback in shaping the dynamics of local circuits, and the resultant computational benefits it provides remains poorly understood. Using rate models of neuronal firing in a network consisting of excitatory, inhibitory and top-down populations, we found that changes in the weight of feedback to inhibitory neurons generated diverse network dynamics and complex transitions between these dynamics. Additionally, modulation of the weight of top-down feedback supported a number of computations, including both pattern separation and oscillatory synchrony. A bifurcation analysis of the network identified a new mechanism by which gamma oscillations could be generated in a model of neural circuits, which we termed Top-down control of Inhibitory Neuron Gamma (TING). We identified the unique roles that top-down feedback of inhibition plays in shaping network dynamics and computation, and the ways in which these dynamics can be deployed to process sensory inputs.Significance StatementThe functional role of feedback projections, connecting excitatory neurons in higher brain areas to inhibitory neurons in primary sensory regions, remains a fundamental open question in neuroscience. Growing evidence suggests that this architecture is recapitulated across a diverse array of sensory systems, ranging from vision to olfaction. Using a rate model of top-down feedback onto inhibition, we found that changes in the weight of feedback support both pattern separation and oscillatory synchrony, including a mechanism by which top-down inputs could entrain gamma oscillations within local networks. These dual functions were accomplished via a codimension-2 bifurcation in the dynamical system. Our results highlight a key role for this top-down feedback, gating inhibition to facilitate often diametrically different local computations.

scholarly journals Cortical circuits implement optimal context integration

2017 ◽  
Author(s):  
Ramakrishnan Iyer ◽  
Stefan Mihalas
Keyword(s):  
Receptive Field ◽  
Large Scale ◽  
Inhibitory Neuron ◽  
Visual Input ◽  
Inhibitory Neurons ◽  
Specific Cell ◽  
Natural Scene ◽  
Cortical Circuits ◽  
Classical Receptive Field ◽  
Excitatory Neurons

Neurons in the primary visual cortex (V1) predominantly respond to a patch of the visual input, their classical receptive field. These responses are modulated by the visual input in the surround [2]. This reflects the fact that features in natural scenes do not occur in isolation: lines, surfaces are generally continuous, and the surround provides context for the information in the classical receptive field. It is generally assumed that the information in the near surround is transmitted via lateral connections between neurons in the same area [2]. A series of large scale efforts have recently described the relation between lateral connectivity and visual evoked responses and found like-to-like connectivity between excitatory neurons [16, 18]. Additionally, specific cell type connectivity for inhibitory neuron types has been described [11, 31]. Current normative models of cortical function relying on sparsity [27], saliency [4] predict functional inhibition between similarly tuned neurons. What computations are consistent with the observed structure of the lateral connections between the excitatory and diverse types of inhibitory neurons?We combined natural scene statistics [24] and mouse V1 neuron responses [7] to compute the lateral connections and computations of individual neurons which optimally integrate information from the classical receptive field with that from the surround by directly implementing Bayes rule. This increases the accuracy of representation of a natural scene under noisy conditions. We show that this network has like-to-like connectivity between excitatory neurons, similar to the observed one [16, 18, 11], and has three types of inhibition: local normalization, surround inhibition and gating of inhibition from the surround - that can be attributed to three classes of inhibitory neurons. We hypothesize that this computation: optimal integration of contextual cues with a gate to ignore context when necessary is a general property of cortical circuits, and the rules constructed for mouse V1 generalize to other areas and species.

scholarly journals Analysis of excitatory and inhibitory neuron types in the inferior colliculus based on Ih properties

2019 ◽  
Vol 121 (6) ◽  
pp. 2126-2139
Author(s):  
Victor Naumov ◽  
Julia Heyd ◽  
Fauve de Arnal ◽  
Ursula Koch
Keyword(s):  
Inferior Colliculus ◽  
Firing Pattern ◽  
Yellow Fluorescent Protein ◽  
Brain Slices ◽  
Inhibitory Neuron ◽  
Gabaergic Neurons ◽  
Membrane Properties ◽  
Firing Patterns ◽  
Glutamatergic Neurons ◽  
Excitatory Neurons

The inferior colliculus (IC) is a large midbrain nucleus that integrates inputs from many auditory brainstem and cortical structures. Despite its prominent role in auditory processing, the various cell types and their connections within the IC are not well characterized. To further separate GABAergic and non-GABAergic neuron types according to their physiological properties, we used a mouse model that expresses channelrhodopsin and enhanced yellow fluorescent protein in all GABAergic neurons and allows identification of GABAergic cells by light stimulation. Neuron types were classified upon electrophysiological measurements of the hyperpolarizing-activated current ( Ih) in acute brain slices of young adult mice. All GABAergic neurons from our sample displayed slow-activating Ih with moderate amplitudes, whereas a subset of excitatory neurons showed fast-activating Ih with large amplitudes. This is in agreement with our finding that immunoreactivity against the fast-gating hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) channel was present around excitatory neurons, whereas the slow-gating HCN4 channel was found perisomatically around most inhibitory neurons. Ih properties and neurotransmitter types were correlated with firing patterns to depolarizing current pulses. All GABAergic neurons displayed adapting firing patterns very similar to the majority of glutamatergic neurons. About 15% of the glutamatergic neurons showed an onset spiking pattern, always in combination with large and fast Ih. We conclude that HCN channel subtypes are differentially distributed in IC neuron types and correlate with neurotransmitter type and firing pattern. In contrast to many other brain regions, membrane properties and firing patterns were similar in GABAergic neurons and about one-third of the excitatory neurons. NEW & NOTEWORTHY Neuron types in the central nucleus of the auditory midbrain are not well characterized regarding their transmitter type, ion channel composition, and firing pattern. The present study shows that GABAergic neurons have slowly activating hyperpolarizing-activated current ( Ih) and an adaptive firing pattern whereas at least four types of glutamatergic neurons exist regarding their Ih properties and firing patterns. Many of the glutamatergic neurons were almost indistinguishable from the GABAergic neurons regarding Ih properties and firing pattern.

scholarly journals Mapping of morpho-electric features to molecular identity of cortical inhibitory neurons

2021 ◽  
Author(s):  
Yann Roussel ◽  
Csaba Verasztó ◽  
Dimitri Rodarie ◽  
Tanguy Damart ◽  
Michael W Reimann ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Inhibitory Neuron ◽  
Inhibitory Neurons ◽  
Cell Type ◽  
Molecular Identity ◽  
Mouse Cortex ◽  
Latent Space ◽  
Cell Type Specific ◽  
Rat Somatosensory Cortex

Knowledge of the cell-type-specific composition of the brain is useful in order to understand the role of each cell type as part of the network. Here, we estimated the composition of the whole cortex in terms of well characterised morphological and electrophysiological inhibitory neuron types (me-types). We derived probabilistic me-type densities from an existing atlas of molecularly defined cell-type densities in the mouse cortex. We used a well-established me-type classification from rat somatosensory cortex to populate the cortex. These me-types were well characterized morphologically and electrophysiologically but they lacked molecular marker identity labels. To extrapolate this missing information, we employed an additional dataset from the Allen Institute for Brain Science containing molecular identity as well as morphological and electrophysiological data for mouse cortical neurons. We first built a latent space based on a number of comparable morphological and electrical features common to both data sources. We then identified 13 morpho-electrical clusters that merged neurons from both datasets while being molecularly homogeneous. The resulting clusters best mirror the molecular identity classification solely using available morpho-electrical features. Finally, we stochastically assigned a molecular identity to a me-type neuron based on the latent space cluster it was assigned to. The resulting mapping was used to derive inhibitory me-types densities in the cortex.

scholarly journals Cortical interneurons ensure maintenance of frequency tuning following adaptation

2017 ◽  
Author(s):  
Ryan G. Natan ◽  
Winnie Rao ◽  
Maria N. Geffen
Keyword(s):  
Frequency Response ◽  
Response Function ◽  
Cortical Neurons ◽  
Frequency Response Function ◽  
Frequency Tuning ◽  
Inhibitory Neurons ◽  
Sensory Stimuli ◽  
Cortical Interneurons ◽  
Excitatory Neurons ◽  
Shape Tuning

AbstractNeurons throughout the sensory pathway are tuned to specific aspects of stimuli. This selectivity is shaped by feedforward and recurrent excitatory-inhibitory interactions. In the auditory cortex (AC), two large classes of interneurons, parvalbumin- (PVs) and somatostatin- positive (SOMs) interneurons, differentially modulate frequency-dependent responses across the frequency response function of excitatory neurons. At the same time, the responsiveness of neurons in AC to sounds is dependent on the temporal context, with the majority of neurons exhibiting adaptation to repeated sounds. Here, we asked whether and how inhibitory neurons shape the frequency response function of excitatory neurons as a function of adaptation to temporal repetition of tones. The effects of suppressing both SOMs and PVs diverged for responses to preferred versus non-preferred frequencies following adaptation. Prior to adaptation, suppressing either SOM or PV inhibition drove both increases and decreases in spiking activity among cortical neurons. After adaptation, suppressing SOM activity caused predominantly disinhibitory effects, whereas suppressing PV activity still evoked bi-directional changes. SOM, but not PV-driven inhibition dynamically modulated frequency tuning as a function of adaptation. Additionally, testing across frequency tuning revealed that, unlike PVs, SOM-driven inhibition exhibited gain-like increases reflective of adaptation. Our findings suggest that distinct cortical interneurons differentially shape tuning to sensory stimuli across the neuronal receptive field, maintaining frequency selectivity of excitatory neurons during adaptation.

scholarly journals Loss of clustered protocadherin diversity alters the spatial distribution of cortical interneurons

2020 ◽  
Author(s):  
Nicholas Gallerani ◽  
Edmund Au
Keyword(s):  
Spatial Distribution ◽  
Limited Range ◽  
Inhibitory Neurons ◽  
Specific Expression ◽  
Spatial Statistical Analysis ◽  
Cell Spacing ◽  
Cortical Interneurons ◽  
Mutant Phenotypes ◽  
Clustered Protocadherins

AbstractCortical interneurons (cINs) are locally-projecting inhibitory neurons that are distributed throughout the cortex. Due to their relatively limited range of influence, their arrangement in the cortex is critical to their function. cINs achieve this arrangement through a process of tangential and radial migration, and apoptosis during development. In this study, we investigated the role of clustered protocadherins (cPcdhs) in establishing the spatial patterning of cINs. cPcdhs are expressed in cINs, and are known to play key functions in cell spacing and cell survival, but their role in cINs is poorly understood. Using spatial statistical analysis, we found that the two main subclasses of cINs, parvalbumin-expressing (PV) and somatostatin-expressing (SST) cINs, are non-randomly spaced within subclass, but randomly with respect to each other. We also found that the relative laminar distribution of each subclass was distinctly altered in whole α- or β-cluster mutants. Examination of perinatal timepoints revealed that the mutant phenotypes emerged relatively late, suggesting that cPcdhs may be acting during cIN morphological elaboration and synaptogenesis. We then analyzed an isoform-specific knockout for pcdh-αc2 and found that it recapitulated the α-cluster knockout, but only in SST cells, suggesting that subtype-specific expression of cPcdh isoforms may help govern subtype-specific spatial distribution.

scholarly journals Role of somatostatin-positive cortical interneurons in the generation of sleep slow waves

2017 ◽  
Author(s):  
Chadd M. Funk ◽  
Kayla Peelman ◽  
Michele Bellesi ◽  
William Marshall ◽  
Chiara Cirelli ◽  
...  
Keyword(s):  
Slow Wave ◽  
Cortical Neurons ◽  
Nrem Sleep ◽  
Slow Waves ◽  
Inhibitory Neurons ◽  
Excitatory Transmission ◽  
Cortical Interneurons ◽  
Somatic Inhibition ◽  
Apical Dendrites

SUMMARYCortical slow waves – the hallmark of NREM sleep - reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer 1 and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation triggers neuronal OFF periods during sleep. Next, we show that chemogenetic activation of SOM+ cells increases slow wave activity (SWA), the slope of individual slow waves, and the duration of NREM sleep; whereas their chemogenetic inhibition decreases SWA and slow wave incidence without changing time spent asleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing. These results indicate that SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.

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