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  • 1
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    Online Resource
    Transynaptic Action of Botulinum Neurotoxin Type A at Central Cholinergic Boutons
    Society for Neuroscience ; 2018
    In:  The Journal of Neuroscience Vol. 38, No. 48 ( 2018-11-28), p. 10329-10337
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 38, No. 48 ( 2018-11-28), p. 10329-10337
    Abstract: Botulinum neurotoxin Type A (BoNT/A) is an effective treatment for several movement disorders, including spasticity and dystonia. BoNT/A acts by cleaving synaptosomal-associated protein of 25 kDa (SNAP-25) at the neuromuscular junction, thus blocking synaptic transmission and weakening overactive muscles. However, not all the therapeutic benefits of the neurotoxin are explained by peripheral neuroparalysis, suggesting an action of BoNT/A on central circuits. Currently, the specific targets of BoNT/A central activity remain unclear. Here, we show that catalytically active BoNT/A is transported to the facial nucleus (FN) after injection into the nasolabial musculature of rats and mice. BoNT/A-mediated cleavage of SNAP-25 in the FN is prevented by intracerebroventricular delivery of antitoxin antibodies, demonstrating that BoNT/A physically leaves the motoneurons to enter second-order neurons. Analysis of intoxicated terminals within the FN shows that BoNT/A is transcytosed preferentially into cholinergic synapses. The cholinergic boutons containing cleaved SNAP-25 are associated with a larger size, suggesting impaired neuroexocytosis. Together, the present findings indicate a previously unrecognized source of reduced motoneuron drive after BoNT/A via blockade of central, excitatory cholinergic inputs. These data highlight the ability of BoNT/A to selectively target and modulate specific central circuits, with consequent impact on its therapeutic effectiveness in movement disorders. SIGNIFICANCE STATEMENT Botulinum neurotoxins are among the most potent toxins known. Despite this, their specific and reversible action prompted their use in clinical practice to treat several neuromuscular pathologies (dystonia, spasticity, muscle spasms) characterized by hyperexcitability of peripheral nerve terminals or even in nonpathological applications (i.e., cosmetic use). Substantial experimental and clinical evidence indicates that not all botulinum neurotoxin Type A (BoNT/A) effects can be explained solely by the local action (i.e., silencing of the neuromuscular junction). In particular, there are cases in which the clinical benefit exceeds the duration of peripheral neurotransmission blockade. In this study, we demonstrate that BoNT/A is transported to facial motoneurons, released, and internalized preferentially into cholinergic terminals impinging onto the motoneurons. Our data demonstrate a direct central action of BoNT/A.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0294-18.2018
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2018
    detail.hit.zdb_id: 1475274-8
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  • 2
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    Antiepileptic Effects of Botulinum Neurotoxin E
    Society for Neuroscience ; 2005
    In:  The Journal of Neuroscience Vol. 25, No. 8 ( 2005-02-23), p. 1943-1951
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 8 ( 2005-02-23), p. 1943-1951
    Abstract: Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4402-04.2005
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2005
    detail.hit.zdb_id: 1475274-8
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  • 3
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    Online Resource
    Transient Synaptic Silencing of Developing Striate Cortex Has Persistent Effects on Visual Function and Plasticity
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 17 ( 2007-04-25), p. 4530-4540
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 17 ( 2007-04-25), p. 4530-4540
    Abstract: Neural circuits in the cerebral cortex are shaped by experience during “critical periods” early in life. For example, visual cortex is immature at the time of eye opening and gradually develops its functional properties during a sensitive period. Very few reports have addressed the role of intrinsic neural activity in cortical maturation. Here we have exploited the bacterial enzyme botulinum neurotoxin E (BoNT/E) to produce a unilateral, reversible blockade of neural activity in rat visual cortex during the sensitive period. BoNT/E is a highly selective protease that interferes with transmitter release via cleavage of the synaptic protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Unilateral, intracortical injections of BoNT/E were made at the time of eye opening and resulted in the silencing of the treated, but not contralateral, hemisphere for a period of 2 weeks. We found that visual acuity was permanently reduced in the blocked hemisphere, and the critical period for ocular dominance plasticity persisted into adulthood. Unexpectedly, these effects extended equally to the contralateral, uninjected side, demonstrating a fundamental role for interhemispheric connections in cortical maturation.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0772-07.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
    detail.hit.zdb_id: 1475274-8
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  • 4
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    Online Resource
    Provision of Brain-Derived Neurotrophic Factor via Anterograde Transport from the Eye Preserves the Physiological Responses of Axotomized Geniculate Neurons
    Society for Neuroscience ; 2003
    In:  The Journal of Neuroscience Vol. 23, No. 1 ( 2003-01-01), p. 287-296
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 23, No. 1 ( 2003-01-01), p. 287-296
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.23-01-00287.2003
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2003
    detail.hit.zdb_id: 1475274-8
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  • 5
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    Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience Vol. 43, No. 23 ( 2023-06-07), p. 4234-4250
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 43, No. 23 ( 2023-06-07), p. 4234-4250
    Abstract: Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions. SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0750-22.2023
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2023
    detail.hit.zdb_id: 1475274-8
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  • 6
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    Narrow and Broad γ Bands Process Complementary Visual Information in Mouse Primary Visual Cortex
    Society for Neuroscience ; 2021
    In:  eneuro Vol. 8, No. 6 ( 2021-11), p. ENEURO.0106-21.2021-
    Details
    In: eneuro, Society for Neuroscience, Vol. 8, No. 6 ( 2021-11), p. ENEURO.0106-21.2021-
    Abstract: γ Band plays a key role in the encoding of visual features in the primary visual cortex (V1). In rodents V1 two ranges within the γ band are sensitive to contrast: a broad γ band (BB) increasing with contrast, and a narrow γ band (NB), peaking at ∼60 Hz, decreasing with contrast. The functional roles of the two bands and the neural circuits originating them are not completely clear yet. Here, we show, combining experimental and simulated data, that in mice V1 (1) BB carries information about high contrast and NB about low contrast; (2) BB modulation depends on excitatory-inhibitory interplay in the cortex, while NB modulation is because of entrainment to the thalamic drive. In awake mice presented with alternating gratings, NB power progressively decreased from low to intermediate levels of contrast where it reached a plateau. Conversely, BB power was constant across low levels of contrast, but it progressively increased from intermediate to high levels of contrast. Furthermore, BB response was stronger immediately after contrast reversal, while the opposite held for NB. These complementary modulations were reproduced by a recurrent excitatory-inhibitory leaky integrate-and-fire network provided that the thalamic inputs were composed of a sustained and a periodic component having complementary sensitivity ranges. These results show that in rodents the thalamic-driven NB plays a specific key role in encoding visual contrast. Moreover, we propose a simple and effective network model of response to visual stimuli in rodents that might help in investigating network dysfunctions of pathologic visual information processing.
    Type of Medium: Online Resource
    ISSN: 2373-2822
    URL: Article
    URL: Article
    DOI: 10.1523/ENEURO.0106-21.2021
    DOI: 10.1523/ENEURO.0106-21.2021.ed1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
    detail.hit.zdb_id: 2800598-3
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  • 7
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    Online Resource
    ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability
    Society for Neuroscience ; 2020
    In:  The Journal of Neuroscience Vol. 40, No. 13 ( 2020-03-25), p. 2776-2788
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    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 40, No. 13 ( 2020-03-25), p. 2776-2788
    Abstract: Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent comorbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Because loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor fasudil. While acute administration of fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition. SIGNIFICANCE STATEMENT In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of X-linked intellectual disability (XLID). Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by Rho-associated protein kinase (ROCK)/protein kinase A (PKA) inhibitor fasudil, a drug already tested on humans. Because seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0462-19.2020
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2020
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Online Resource
    Activation of Rho GTPases Triggers Structural Remodeling and Functional Plasticity in the Adult Rat Visual Cortex
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 42 ( 2011-10-19), p. 15163-15172
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 42 ( 2011-10-19), p. 15163-15172
    Abstract: A classical example of age-dependent plasticity is ocular dominance (OD) plasticity, triggered by monocular deprivation (MD). Sensitivity of cortical circuits to a brief period of MD is maximal in juvenile animals and downregulated in adult age. It remains unclear whether a reduced potential for morphological remodeling underlies this downregulation of physiological plasticity in adulthood. Here we have tested whether stimulation of structural rearrangements is effective in promoting experience-dependent plasticity in adult age. We have exploited a bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), that regulates actin dynamics and structure of neuronal processes via a persistent activation of Rho GTPases. Injection of CNF1 into the adult rat visual cortex triggered a long-lasting activation of the Rho GTPase Rac1, with a consequent increase in spine density and length in pyramidal neurons. Adult rats treated with CNF1, but not controls, showed an OD shift toward the open eye after MD. CNF1-mediated OD plasticity was selectively attributable to the enhancement of open-eye responses, whereas closed-eye inputs were unaffected. This effect correlated with an increased density of geniculocortical terminals in layer IV of monocularly deprived, CNF1-treated rats. Thus, Rho GTPase activation reinstates OD plasticity in the adult cortex via the potentiation of more active inputs from the open eye. These data establish a direct link between structural remodeling and functional plasticity and demonstrate a role for Rho GTPases in brain plasticity in vivo . The plasticizing effects of Rho GTPase activation may be exploited to promote brain repair.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2617-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
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  • 9
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    Online Resource
    Evidence for Anterograde Transport and Transcytosis of Botulinum Neurotoxin A (BoNT/A)
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 44 ( 2011-11-02), p. 15650-15659
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 44 ( 2011-11-02), p. 15650-15659
    Abstract: Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that blocks synaptic transmission via the cleavage of SNAP-25 (synaptosomal-associated protein of 25 kDa). BoNT/A is successfully used in clinical neurology for the treatment of several neuromuscular pathologies and pain syndromes. Despite its widespread use, relatively little is known on BoNT/A intracellular trafficking in neurons. Using the visual pathway as a model system, here we show that catalytically active BoNT/A is capable of undergoing anterograde axonal transport and transcytosis. Following BoNT/A injection into the rat eye, significant levels of BoNT/A-cleaved SNAP-25 appeared in the retinorecipient layers of the superior colliculus (SC). Anterograde propagation of BoNT/A effects required axonal transport, ruling out a systemic spread of the toxin. Cleaved SNAP-25 was present in presynaptic structures of the tectum, but retinal terminals were devoid of the immunoreactivity, indicative of transcytosis. Experiments based on sequential administration of BoNT/A and BoNT/E showed a persistent catalytic activity of BoNT/A in tectal cells following its injection into the retina. Our findings demonstrate that catalytically active BoNT/A is anterogradely transported from the eye to the SC and transcytosed to tectal synapses. These data are important for a more complete understanding of the mechanisms of action of BoNT/A.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2618-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
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  • 10
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    Online Resource
    The Chemokine CCL2 Mediates the Seizure-enhancing Effects of Systemic Inflammation
    Society for Neuroscience ; 2016
    In:  The Journal of Neuroscience Vol. 36, No. 13 ( 2016-03-30), p. 3777-3788
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 36, No. 13 ( 2016-03-30), p. 3777-3788
    Abstract: Epilepsy is a chronic disorder characterized by spontaneous recurrent seizures. Brain inflammation is increasingly recognized as a critical factor for seizure precipitation, but the molecular mediators of such proconvulsant effects are only partly understood. The chemokine CCL2 is one of the most elevated inflammatory mediators in patients with pharmacoresistent epilepsy, but its contribution to seizure generation remains unexplored. Here, we show, for the first time, a crucial role for CCL2 and its receptor CCR2 in seizure control. We imposed a systemic inflammatory challenge via lipopolysaccharide (LPS) administration in mice with mesial temporal lobe epilepsy. We found that LPS dramatically increased seizure frequency and upregulated the expression of many inflammatory proteins, including CCL2. To test the proconvulsant role of CCL2, we administered systemically either a CCL2 transcription inhibitor (bindarit) or a selective antagonist of the CCR2 receptor (RS102895). We found that interference with CCL2 signaling potently suppressed LPS-induced seizures. Intracerebral administration of anti-CCL2 antibodies also abrogated LPS-mediated seizure enhancement in chronically epileptic animals. Our results reveal that CCL2 is a key mediator in the molecular pathways that link peripheral inflammation with neuronal hyperexcitability. SIGNIFICANCE STATEMENT Substantial evidence points to a role for inflammation in epilepsy, but currently there is little insight as to how inflammatory pathways impact on seizure generation. Here, we examine the molecular mediators linking peripheral inflammation with seizure susceptibility in mice with mesial temporal lobe epilepsy. We show that a systemic inflammatory challenge via lipopolysaccharide administration potently enhances seizure frequency and upregulates the expression of the chemokine CCL2. Remarkably, selective pharmacological interference with CCL2 or its receptor CCR2 suppresses lipopolysaccharide-induced seizure enhancement. Thus, CCL2/CCR2 signaling plays a key role in linking systemic inflammation with seizure susceptibility.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0451-15.2016
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2016
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