scholarly journals Cellular and Synaptic Phenotype Compensations Limit Circuit Disruption in Fmr1-KO Mouse Layer 4 Barrel Cortex but Fail to Prevent Deficits in Information Processing

2018 ◽  
Author(s):  
Aleksander P.F. Domanski ◽  
Sam A. Booker ◽  
David J.A. Wyllie ◽  
John T.R. Isaac ◽  
Peter C. Kind
Keyword(s):  
Sensory Processing ◽  
Knockout Mice ◽  
Barrel Cortex ◽  
Fragile X ◽  
Neuronal Function ◽  
Sensory Hypersensitivity ◽  
Layer 4 ◽  
Network Simulations ◽  
Sensory Encoding ◽  
Critical Process

AbstractSensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). However, how developmental changes in neuronal function ultimately culminate in the network dysfunction that underlies sensory hypersensitivities is not known. To address this, we studied the layer 4 barrel cortex circuit in Fmr1 knockout mice, a critical sensory processing circuit in this mouse model of FXS. By systematically studying cellular and synaptic properties of layer 4 neurons and combining with cellular and network simulations, we explored how the array of phenotypes in Fmr1 knockout produce circuit pathology during development that result in sensory processing dysfunction. We show that many of the cellular and synaptic pathologies in Fmr1 knockout mice are antagonistic, mitigating circuit dysfunction, and hence can be regarded as compensatory to the primary pathology. Despite this compensation, the layer 4 network in the Fmr1 knockout exhibits significant alterations in spike output in response to ascending thalamocortical input that we show results in impaired sensory encoding. We suggest that it is this developmental loss of layer 4 sensory encoding precision that drives subsequent developmental alterations in layer 4 – layer 2/3 connectivity and plasticity observed in the Fmr1 knockout, and is a critical process producing sensory hypersensitivity.

scholarly journals Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Aleksander P. F. Domanski ◽  
Sam A. Booker ◽  
David J. A. Wyllie ◽  
John T. R. Isaac ◽  
Peter C. Kind
Keyword(s):  
Neurodevelopmental Disorders ◽  
Barrel Cortex ◽  
Fragile X ◽  
Developmental Changes ◽  
Neuronal Function ◽  
Sensory Hypersensitivity ◽  
Layer 2 ◽  
Layer 4 ◽  
Network Simulations ◽  
Sensory Encoding

Abstract Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity.

scholarly journals Contribution of interneuron subtype-specific GABAergic signalling to emergent sensory processing in somatosensory whisker barrel cortex in mouse

2021 ◽  
Author(s):  
Liad J. Baruchin ◽  
Michael M. Kohl ◽  
Simon J.B Butt
Keyword(s):  
Sensory Processing ◽  
Barrel Cortex ◽  
Sensory Information ◽  
Gaba Release ◽  
Gabaergic Interneuron ◽  
Dependent Manner ◽  
Sensory Adaptation ◽  
Layer 4 ◽  
Evoked Activity ◽  
Sensory Evoked

AbstractMammalian neocortex is important for conscious processing of sensory information. Fundamental to this function is balanced glutamatergic and GABAergic signalling. Yet little is known about how this interaction arises in the developing forebrain despite increasing insight into early GABAergic interneuron (IN) circuits. To further study this, we assessed the contribution of specific INs to the development of sensory processing in the mouse whisker barrel cortex. Specifically we explored the role of INs in speed coding and sensory adaptation. In wild-type animals, both speed processing and adaptation were present as early as the layer 4 critical period of plasticity, and showed refinement over the period leading to active whisking onset. We then conditionally silenced action-potential-dependent GABA release in either somatostatin (SST) or vasoactive intestinal peptide (VIP) INs. These genetic manipulations influenced both spontaneous and sensory-evoked activity in an age and layer-dependent manner. Silencing SST+ INs reduced early spontaneous activity and abolished facilitation in sensory adaptation observed in control pups. In contrast, VIP+ IN silencing had an effect towards the onset of active whisking. Silencing either IN subtype had no effect on speed coding. Our results reveal how these IN subtypes differentially contribute to early sensory processing over the first few postnatal weeks.

scholarly journals Sensory Processing Phenotypes in Fragile X Syndrome

ASN NEURO ◽  
2018 ◽  
Vol 10 ◽  
pp. 175909141880109 ◽  
Author(s):  
Maham Rais ◽  
Devin K. Binder ◽  
Khaleel A. Razak ◽  
Iryna M. Ethell
Keyword(s):  
Animal Models ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Gene Knockout ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Acoustic Startle ◽  
Numerical Sequence ◽  
Somatosensory Processing ◽  
Sensory Hypersensitivity

Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability. It is a leading known genetic cause of autism. In addition to cognitive, social, and communication deficits, humans with FXS demonstrate abnormal sensory processing including sensory hypersensitivity. Sensory hypersensitivity commonly manifests as auditory, tactile, or visual defensiveness or avoidance. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity, impaired habituation to repeated sounds, and reduced auditory attention in humans with FXS. Children with FXS also exhibit significant visuospatial impairments. Studies in infants and toddlers with FXS have documented impairments in processing texture-defined motion stimuli, temporal flicker, perceiving ordinal numerical sequence, and the ability to maintain the identity of dynamic object information during occlusion. Consistent with the observations in humans with FXS, fragile X mental retardation 1 ( Fmr1) gene knockout (KO) rodent models of FXS also show seizures, abnormal visual-evoked responses, auditory hypersensitivity, and abnormal processing at multiple levels of the auditory system, including altered acoustic startle responses. Among other sensory symptoms, individuals with FXS exhibit tactile defensiveness. Fmr1 KO mice also show impaired encoding of tactile stimulation frequency and larger size of receptive fields in the somatosensory cortex. Since sensory deficits are relatively more tractable from circuit mechanisms and developmental perspectives than more complex social behaviors, the focus of this review is on clinical, functional, and structural studies that outline the auditory, visual, and somatosensory processing deficits in FXS. The similarities in sensory phenotypes between humans with FXS and animal models suggest a likely conservation of basic sensory processing circuits across species and may provide a translational platform to not just develop biomarkers but also to understand underlying mechanisms. We argue that preclinical studies in animal models of FXS can facilitate the ongoing search for new therapeutic approaches in FXS by understanding mechanisms of basic sensory processing circuits and behaviors that are conserved across species.

scholarly journals Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome

2008 ◽  
Vol 100 (5) ◽  
pp. 2615-2626 ◽  
Author(s):  
Jay R. Gibson ◽  
Aundrea F. Bartley ◽  
Seth A. Hays ◽  
Kimberly M. Huber
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Barrel Cortex ◽  
Feedback Inhibition ◽  
Fragile X ◽  
Inhibitory Neurons ◽  
Neurological Deficits ◽  
Membrane Excitability ◽  
Up States ◽  
Layer 4

Despite the pronounced neurological deficits associated with mental retardation and autism, it is unknown if altered neocortical circuit function occurs in these prevalent disorders. Here we demonstrate specific alterations in local synaptic connections, membrane excitability, and circuit activity of defined neuron types in sensory neocortex of the mouse model of Fragile X Syndrome—the Fmr1 knockout (KO). Overall, these alterations result in hyperexcitability of neocortical circuits in the Fmr1 KO. Specifically, we observe a substantial deficit in local excitatory drive (∼50%) targeting fast-spiking (FS) inhibitory neurons in layer 4 of somatosensory, barrel cortex. This persists until at least 4 wk of age suggesting it may be permanent. In contrast, monosynaptic GABAergic synaptic transmission was unaffected. Overall, these changes indicate that local feedback inhibition in neocortical layer 4 is severely impaired in the Fmr1 KO mouse. An increase in the intrinsic membrane excitability of excitatory neurons may further contribute to hyperexcitability of cortical networks. In support of this idea, persistent neocortical circuit activity, or UP states, elicited by thalamic stimulation was longer in duration in the Fmr1 KO mouse. In addition, network inhibition during the UP state was less synchronous, including a 14% decrease in synchrony in the gamma frequency range (30–80 Hz). These circuit changes may be involved in sensory stimulus hypersensitivity, epilepsy, and cognitive impairment associated with Fragile X and autism.

scholarly journals Contribution of Interneuron Subtype-Specific GABAergic Signaling to Emergent Sensory Processing in Mouse Somatosensory Whisker Barrel Cortex

2021 ◽  
Author(s):  
Liad J Baruchin ◽  
Filippo Ghezzi ◽  
Michael M Kohl ◽  
Simon J B Butt
Keyword(s):  
Sensory Processing ◽  
Barrel Cortex ◽  
Sensory Information ◽  
Gaba Release ◽  
Gabaergic Interneuron ◽  
Dependent Manner ◽  
Sensory Adaptation ◽  
Genetic Manipulations ◽  
Layer 4 ◽  
Sensory Evoked

Abstract Mammalian neocortex is important for conscious processing of sensory information with balanced glutamatergic and GABAergic signaling fundamental to this function. Yet little is known about how this interaction arises despite increasing insight into early GABAergic interneuron (IN) circuits. To study this, we assessed the contribution of specific INs to the development of sensory processing in the mouse whisker barrel cortex, specifically the role of INs in early speed coding and sensory adaptation. In wild-type animals, both speed processing and adaptation were present as early as the layer 4 critical period of plasticity and showed refinement over the period leading to active whisking onset. To test the contribution of IN subtypes, we conditionally silenced action-potential-dependent GABA release in either somatostatin (SST) or vasoactive intestinal peptide (VIP) INs. These genetic manipulations influenced both spontaneous and sensory-evoked cortical activity in an age- and layer-dependent manner. Silencing SST + INs reduced early spontaneous activity and abolished facilitation in sensory adaptation observed in control pups. In contrast, VIP + IN silencing had an effect towards the onset of active whisking. Silencing either IN subtype had no effect on speed coding. Our results show that these IN subtypes contribute to early sensory processing over the first few postnatal weeks.

scholarly journals Loss of Calretinin in L5a impairs the formation of the barrel cortex leading to abnormal whisker-mediated behaviors

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Mingzhao Su ◽  
Junhua Liu ◽  
Baocong Yu ◽  
Kaixing Zhou ◽  
Congli Sun ◽  
...  
Keyword(s):  
Information Integration ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Sensory Information ◽  
Membrane Excitability ◽  
Novelty Preference ◽  
Layer 4 ◽  
Dendritic Complexity ◽  
Cortex System

AbstractThe rodent whisker-barrel cortex system has been established as an ideal model for studying sensory information integration. The barrel cortex consists of barrel and septa columns that receive information input from the lemniscal and paralemniscal pathways, respectively. Layer 5a is involved in both barrel and septa circuits and play a key role in information integration. However, the role of layer 5a in the development of the barrel cortex remains unclear. Previously, we found that calretinin is dynamically expressed in layer 5a. In this study, we analyzed calretinin KO mice and found that the dendritic complexity and length of layer 5a pyramidal neurons were significantly decreased after calretinin ablation. The membrane excitability and excitatory synaptic transmission of layer 5a neurons were increased. Consequently, the organization of the barrels was impaired. Moreover, layer 4 spiny stellate cells were not able to properly gather, leading to abnormal formation of barrel walls as the ratio of barrel/septum size obviously decreased. Calretinin KO mice exhibited deficits in exploratory and whisker-associated tactile behaviors as well as social novelty preference. Our study expands our knowledge of layer 5a pyramidal neurons in the formation of barrel walls and deepens the understanding of the development of the whisker-barrel cortex system.

scholarly journals Critical Period Plasticity Is Disrupted in the Barrel Cortex of Fmr1 Knockout Mice

Neuron ◽  
2010 ◽  
Vol 65 (3) ◽  
pp. 385-398 ◽  
Author(s):  
Emily G. Harlow ◽  
Sally M. Till ◽  
Theron A. Russell ◽  
Lasani S. Wijetunge ◽  
Peter Kind ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Critical Period ◽  
Barrel Cortex

Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures

2009 ◽  
Vol 76 (1) ◽  
pp. 18-24 ◽  
Author(s):  
Laura K. K. Pacey ◽  
Scott P. Heximer ◽  
David R. Hampson
Keyword(s):  
Knockout Mice ◽  
Gabab Receptor ◽  
Fragile X ◽  
Audiogenic Seizures

Long-term potentiation in the hippocampus of fragile X knockout mice

1996 ◽  
Vol 64 (2) ◽  
pp. 246-251 ◽  
Author(s):  
Jean-Marie Godfraind ◽  
Edwin Reyniers ◽  
Kristel De Boulle ◽  
Rudi D'Hooge ◽  
Peter P. De Deyn ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Fragile X ◽  
Long Term Potentiation ◽  
Term Potentiation

scholarly journals The Excitatory Neuronal Network of Rat Layer 4 Barrel Cortex

2000 ◽  
Vol 20 (20) ◽  
pp. 7579-7586 ◽  
Author(s):  
Carl C. H. Petersen ◽  
Bert Sakmann
Keyword(s):  
Neuronal Network ◽  
Barrel Cortex ◽  
Layer 4
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