Gephyrin-Lacking PV Synapses on Neocortical Pyramidal Neurons

Kuljis, Dika; Ray, Ajit; Wegner, Waja; Bowman, Ryan; Madison, Daniel V.; Willig, Katrin I.; Barth, Alison L.

doi:10.3390/ijms221810032

Cited by 4 publications

(4 citation statements)

References 120 publications

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“…In vivo dendritic imaging does not capture all inhibitory synapses, such as the soma targeting parvalbumin neurons, 82 and changes to ion channel composition. Furthermore, the mouse model used in this study overexpresses amyloid precursor protein with familial AD mutations, 70 and whether non-overexpressing mice show similar phenotypes remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions

et al. 2023

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“…We took advantage of these well-documented changes to develop quantitative, fluorescence-based anatomic methods for detection of structural correlates of plasticity during learning. Fluorescence-based synapse analysis leverages the extended color palette of fluorescent proteins as well as the broad availability of confocal microscopy for analysis, and molecular genetic reagents can selectively label targeted cell types, critical for defining circuit-specific changes (Gross et al, 2013;Fortin et al, 2014;Kuljis et al, 2019Kuljis et al, , 2021Bensussen et al, 2020;Graves et al, 2021). In addition, compared with electron microscopy (EM; Bock et al, 2011;Kasthuri et al, 2015;Rodriguez-Moreno et al, 2018), fluorescence-based analyses are amenable to rapid analysis of large numbers of subjects, critical for studies where there is substantial variability in synapse density (Chandrasekaran et al, 2015) or behavior (Bernhard et al, 2020;Gilad and Helmchen, 2020).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Fluorescence Analysis Reveals Dendrite-Specific Thalamocortical Plasticity in L5 Pyramidal Neurons during Learning

et al. 2022

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High-throughput anatomic data can stimulate and constrain new hypotheses about how neural circuits change in response to experience. Here, we use fluorescence-based reagents for presynaptic and postsynaptic labeling to monitor changes in thalamocortical synapses onto different compartments of layer 5 (L5) pyramidal (Pyr) neurons in somatosensory (barrel) cortex from mixed-sex mice during whisker-dependent learning (Audette et al., 2019). Using axonal fills and molecular-genetic tags for synapse identification in fixed tissue from Rbp4-Cre transgenic mice, we found that thalamocortical synapses from the higher-order posterior medial thalamic nucleus showed rapid morphologic changes in both presynaptic and postsynaptic structures at the earliest stages of sensory association training. Detected increases in thalamocortical synaptic size were compartment specific, occurring selectively in the proximal dendrites onto L5 Pyr and not at inputs onto their apical tufts in L1. Both axonal and dendritic changes were transient, normalizing back to baseline as animals became expert in the task. Anatomical measurements were corroborated by electrophysiological recordings at different stages of training. Thus, fluorescence-based analysis of input- and target-specific synapses can reveal compartment-specific changes in synapse properties during learning.SIGNIFICANCE STATEMENTSynaptic changes underlie the cellular basis of learning, experience, and neurologic diseases. Neuroanatomical methods to assess synaptic plasticity can provide critical spatial information necessary for building models of neuronal computations during learning and experience but are technically and fiscally intensive. Here, we describe a confocal fluorescence microscopy–based analytical method to assess input, cell type, and dendritic location-specific synaptic plasticity in a sensory learning assay. Our method not only confirms prior electrophysiological measurements but allows us to predict functional strength of synapses in a pathway-specific manner. Our findings also indicate that changes in primary sensory cortices are transient, occurring during early learning. Fluorescence-based synapse identification can be an efficient and easily adopted approach to study synaptic changes in a variety of experimental paradigms.

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“…In gephyrin deficient mice, there is an almost total absence of glycinergic neurotransmission, which is not compensated for by GABAergic transmission (which remains functional) [ 17 , 133 , 147 ] alongside severe effects on MN survival, morphology and muscular innervation [ 133 ]. These results are also suggestive of different postsynaptic roles for gephyrin at GABAergic and glycinergic synapses, which may also depend on neural region [ 148 , 149 ] and pathophysiological factors [ 150 ]. Additional roles for gephyrin impairment in various behavioural brain disorders have also been postulated [ 151 ].…”

Section: Inhibitory Neurotransmissionmentioning

confidence: 96%

Inhibitory Synaptic Influences on Developmental Motor Disorders

Fogarty

2023

IJMS

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During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to discuss the differences in limb and respiratory neuromotor control. We then investigate the influences that GABAergic and glycinergic neurotransmission has on two major developmental neuromotor disorders: Rett syndrome and spastic cerebral palsy. We present these two syndromes in order to contrast the approaches to disease mechanism and therapy. While both conditions have motor dysfunctions at their core, one condition Rett syndrome, despite having myriad symptoms, has scientists focused on the breathing abnormalities and their alleviation—to great clinical advances. By contrast, cerebral palsy remains a scientific quagmire or poor definitions, no widely adopted model and a lack of therapeutic focus. We conclude that the sheer abundance of diversity of inhibitory neurotransmitter targets should provide hope for intractable conditions, particularly those that exhibit broad spectra of dysfunction—such as spastic cerebral palsy and Rett syndrome.

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Gephyrin-Lacking PV Synapses on Neocortical Pyramidal Neurons

Cited by 4 publications

References 120 publications

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions

Quantitative Fluorescence Analysis Reveals Dendrite-Specific Thalamocortical Plasticity in L5 Pyramidal Neurons during Learning

Inhibitory Synaptic Influences on Developmental Motor Disorders

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