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1.
Diabet Med ; 40(7): e15100, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36999620

RESUMEN

AIMS: Severe hypoglycaemia requiring emergency medical services remains prevalent despite advances in all aspects of diabetes self-management. Real-time continuous glucose monitoring (RTCGM) technologies can reduce the risk of severe hypoglycaemia for adults with type 1 diabetes, but the impact of these devices has not been assessed in the acute phase after an episode of severe hypoglycaemia. METHODS: We recruited and randomised 35 adults with type 1 diabetes in the acute period after an episode of severe hypoglycaemia requiring emergency medical services and randomised participants to RTCGM with alerts and alarms, or usual care with self-monitored blood glucose for 12 weeks with intermittent blinded CGM. The primary outcome was the difference between groups in percentage time spent in hypoglycaemia (≤3.0 mmol/L, 55 mg/dL). RESULTS: Thirty participants completed the study (median (IQR) age, duration of diabetes, and BMI was 43 (36-56) years, 26 (19-37) years, and 24.9 (21.9-29.0) kg/m2 , respectively). Sufficient CGM data was available for 15 participants in RT-CGM group and 8 in SMBG group for the primary outcome analysis. The RTCGM group had a significantly larger reduction in exposure to glucose below 3.0 mmol/L (RTCGM -0.16 [-1.23 to 0.01] vs. SMBG 1.58 [0.41 to 3.48], p = 0.03) and episodes of nocturnal hypoglycaemia (RT-CGM -0.03 [-0.15 to 0.02] vs. SMBG 0.05 [-0.03 to 0.40], p = 0.02). Episodes of severe hypoglycaemia were significantly lower in the RTCGM group (RTCGM 0.0 vs. SMBG 4.0, p 0.04). CONCLUSIONS: RTCGM implemented acutely after an episode of severe hypoglycaemia is feasible and clinically effective with important implications for hypoglycaemia management pathways and self-monitoring cost effectiveness.


Asunto(s)
Diabetes Mellitus Tipo 1 , Hipoglucemia , Adulto , Humanos , Persona de Mediana Edad , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Hipoglucemiantes/uso terapéutico , Automonitorización de la Glucosa Sanguínea , Hemoglobina Glucada , Hipoglucemia/prevención & control
2.
Diabet Med ; 38(11): e14654, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34278609

RESUMEN

AIMS/HYPOTHESIS: Out-of-hospital hypoglycaemia is a common complication for individuals with diabetes mellitus and represents a significant burden to emergency medical services (EMS). We aim to identify the factors associated with receiving parenteral treatment and hospital conveyance. METHODS: We retrospectively analysed a 6-month data set of all London EMS hypoglycaemia. Individuals with a known diabetes diagnosis were included in our analysis and stratified as either having type 1 diabetes or type 2 diabetes. RESULTS: A total of 2862 incidents occurred within the area served by London Ambulance Service between January and June 2018. Fifty percent of incidents required parenteral treatment (intravenous glucose or intramuscular glucagon) and were conveyed to hospital. A higher arrival of blood glucose, intact consciousness and receiving oral glucose treatment were all negative predictors for requiring parenteral therapy. Forty-three percent of incidents were labelled as 'hypoglycaemia' by the EMS call handler, and greater odds of hospitalisation were observed among incidents that received parenteral treatment (OR 2.52 [95% CI 1.46, 4.33] p < 0.01) and individuals with type 2 diabetes (OR 2.67 [95% CI 1.52, 4.71] p < 0.01). Repeated callouts from 2% (n = 50) of individuals accounted for 10% (286) of all incidents attended, and 56.4% of individuals attended by EMS on more than one occasion had type 1 diabetes. CONCLUSIONS/INTERPRETATION: Severe hypoglycaemia requiring emergency service attendance remains common, as does the requirement for parenteral therapy and conveyance to hospital. Early intervention, education and improved accessibility to risk prevention strategies may reduce the necessity for emergency parenteral treatment and hospitalisation, especially among individuals suffering from recurrent hypoglycaemia and high-risk individuals with type 2 diabetes.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Servicios Médicos de Urgencia , Hipoglucemia/epidemiología , Población Urbana , Anciano , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemia/sangre , Hipoglucemia/etiología , Incidencia , Londres/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
3.
Mov Disord ; 32(7): 1035-1046, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28394013

RESUMEN

BACKGROUND: Recent studies support the therapeutic utility of repetitive transcranial magnetic stimulation in Parkinson's disease (PD), whose progression is correlated with loss of corticostriatal long-term potentiation and long-term depression. Glial cell activation is also a feature of PD that is gaining increasing attention in the field because astrocytes play a role in chronic neuroinflammatory responses but are also able to manage dopamine (DA) levels. METHODS: Intermittent theta-burst stimulation protocol was applied to study the effect of therapeutic neuromodulation on striatal DA levels measured by means of in vivo microdialysis in 6-hydroxydopamine-hemilesioned rats. Effects on corticostriatal synaptic plasticity were studied through in vitro intracellular and whole-cell patch clamp recordings while stepping test and CatWalk were used to test motor behavior. Immunohistochemical analyses were performed to analyze morphological changes in neurons and glial cells. RESULTS: Acute theta-burst stimulation induced an increase in striatal DA levels in hemiparkinsonian rats, 80 minutes post-treatment, correlated with full recovery of plasticity and amelioration of motor performances. With the same timing, immediate early gene activation was restricted to striatal spiny neurons. Intense astrocytic and microglial responses were also significantly reduced 80 minutes following theta-burst stimulation. CONCLUSION: Taken together, these results provide a first glimpse on physiological adaptations that occur in the parkinsonian striatum following intermittent theta-burst stimulation and may help to disclose the real potential of this technique in treating PD and preventing DA replacement therapy-associated disturbances. © 2017 International Parkinson and Movement Disorder Society.


Asunto(s)
Astrocitos/fisiología , Corteza Cerebral , Cuerpo Estriado , Dopamina/metabolismo , Microglía/fisiología , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , Trastornos Parkinsonianos/terapia , Estimulación Magnética Transcraneal/métodos , Adrenérgicos/farmacología , Animales , Conducta Animal/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Genes Inmediatos-Precoces/fisiología , Masculino , Microdiálisis , Oxidopamina/farmacología , Trastornos Parkinsonianos/inducido químicamente , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Ritmo Teta/fisiología
4.
Neurobiol Dis ; 86: 140-53, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26639853

RESUMEN

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Discinesia Inducida por Medicamentos/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Trastornos Parkinsonianos/complicaciones , Piperazinas/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Animales , Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/psicología , Levodopa , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Wistar , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
5.
Proc Natl Acad Sci U S A ; 110(46): E4375-84, 2013 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-24170862

RESUMEN

Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.


Asunto(s)
Cuerpo Estriado/fisiología , Neuronas Dopaminérgicas/trasplante , Plasticidad Neuronal/fisiología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/terapia , Análisis de Varianza , Animales , Western Blotting , Dopamina/metabolismo , Embrión de Mamíferos/citología , Femenino , Inmunohistoquímica , Potenciación a Largo Plazo/fisiología , Actividad Motora/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Proc Natl Acad Sci U S A ; 108(52): 20998-1003, 2011 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-22171003

RESUMEN

Coupling of spindle orientation to cellular polarity is a prerequisite for epithelial asymmetric cell divisions. The current view posits that the adaptor Inscuteable (Insc) bridges between Par3 and the spindle tethering machinery assembled on NuMALGNGαi(GDP), thus triggering apico-basal spindle orientation. The crystal structure of the Drosophila ortholog of LGN (known as Pins) in complex with Insc reveals a modular interface contributed by evolutionary conserved residues. The structure also identifies a positively charged patch of LGN binding to an invariant EPE-motif present on both Insc and NuMA. In vitro competition assays indicate that Insc competes with NuMA for LGN binding, displaying a higher affinity, and that it is capable of opening the LGN conformational switch. The finding that Insc and NuMA are mutually exclusive interactors of LGN challenges the established model of force generators assembly, which we revise on the basis of the newly discovered biochemical properties of the intervening components.


Asunto(s)
División Celular Asimétrica/fisiología , Proteínas del Citoesqueleto/genética , Proteínas de Drosophila/genética , Células Epiteliales/fisiología , Inhibidores de Disociación de Guanina Nucleótido/genética , Proteínas de la Membrana/genética , Modelos Moleculares , Proteínas del Tejido Nervioso/genética , Secuencia de Aminoácidos , Animales , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Unión Competitiva/fisiología , Proteínas de Ciclo Celular , Polaridad Celular/fisiología , Pollos , Cromatografía de Afinidad , Cromatografía por Intercambio Iónico , Cristalización , Proteínas del Citoesqueleto/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Electroforesis en Gel de Poliacrilamida , Polarización de Fluorescencia , Inhibidores de Disociación de Guanina Nucleótido/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Oryzias , Conformación Proteica , Alineación de Secuencia , Huso Acromático/fisiología , Electricidad Estática , Xenopus laevis , Pez Cebra
7.
J Neurosci ; 32(49): 17921-31, 2012 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-23223310

RESUMEN

Dopamine replacement with levodopa (L-DOPA) represents the mainstay of Parkinson's disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as L-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem inPDtreatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to L-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with L-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.


Asunto(s)
Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Trastornos Parkinsonianos/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Benzotiazoles/efectos adversos , Benzotiazoles/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/complicaciones , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/fisiopatología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Levodopa/efectos adversos , Levodopa/farmacología , Masculino , Neuronas/metabolismo , Neuronas/fisiología , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Pramipexol , Ratas , Ratas Wistar , Receptores de Dopamina D3/metabolismo
8.
Brain ; 135(Pt 6): 1884-99, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22561640

RESUMEN

Although patients with Parkinson's disease show impairments in cognitive performance even at the early stage of the disease, the synaptic mechanisms underlying cognitive impairment in this pathology are unknown. Hippocampal long-term potentiation represents the major experimental model for the synaptic changes underlying learning and memory and is controlled by endogenous dopamine. We found that hippocampal long-term potentiation is altered in both a neurotoxic and transgenic model of Parkinson's disease and this plastic alteration is associated with an impaired dopaminergic transmission and a decrease of NR2A/NR2B subunit ratio in synaptic N-methyl-d-aspartic acid receptors. Deficits in hippocampal-dependent learning were also found in hemiparkinsonian and mutant animals. Interestingly, the dopamine precursor l-DOPA was able to restore hippocampal synaptic potentiation via D1/D5 receptors and to ameliorate the cognitive deficit in parkinsonian animals suggesting that dopamine-dependent impairment of hippocampal long-term potentiation may contribute to cognitive deficits in patients with Parkinson's disease.


Asunto(s)
Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Trastornos de la Memoria/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Análisis de Varianza , Animales , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Benserazida/farmacología , Benserazida/uso terapéutico , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/genética , Modelos Animales de Enfermedad , Dopamina/metabolismo , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria/efectos de los fármacos , Humanos , Levodopa/farmacología , Levodopa/uso terapéutico , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/genética , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microdiálisis/métodos , Mutación/genética , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Técnicas de Placa-Clamp , Cintigrafía , Ratas , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Simpaticolíticos/toxicidad , Sinaptosomas/diagnóstico por imagen , Sinaptosomas/efectos de los fármacos , Tritio/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/genética
9.
Learn Mem ; 19(5): 211-8, 2012 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-22523415

RESUMEN

The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed a novel behavioral procedure to study object memory load in mice by progressively increasing the stimulus set size in the spontaneous object recognition task. Using this procedure, we demonstrated that naive mice have a memory span, which is the number of elements they can remember for a short-time interval, of about six objects. Then, we showed that excitotoxic selective lesions of the dorsal hippocampus did not impair novel object discrimination in the condition of low memory load. In contrast, the same lesion impaired novel object discrimination in the high memory load condition, and reduced the object memory span to four objects. These results have important heuristic and clinical implications because they open new perspective toward the understanding of the role of the hippocampus in item memory and in memory span deficits occurring in human pathologies, such as Alzheimer's disease and schizophrenia.


Asunto(s)
Hipocampo/fisiología , Reconocimiento en Psicología/fisiología , Animales , Masculino , Ratones
10.
J Neurosci ; 31(35): 12513-22, 2011 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-21880913

RESUMEN

Striatal medium spiny neurons (MSNs) are divided into two subpopulations exerting distinct effects on motor behavior. Transgenic mice carrying bacterial artificial chromosome (BAC) able to confer cell type-specific expression of enhanced green fluorescent protein (eGFP) for dopamine (DA) receptors have been developed to characterize differences between these subpopulations. Analysis of these mice, in contrast with original pioneering studies, showed that striatal long-term depression (LTD) was expressed in indirect but not in the direct pathway MSNs. To address this mismatch, we applied a new approach using combined BAC technology and receptor immunohistochemistry. We demonstrate that, in physiological conditions, DA-dependent LTD is expressed in both pathways showing that the lack of synaptic plasticity found in D(1) eGFP mice is associated to behavioral deficits. Our findings suggest caution in the use of this tool and indicate that the "striatal segregation" hypothesis might not explain all synaptic dysfunctions in Parkinson's disease.


Asunto(s)
Cuerpo Estriado/patología , Dopamina/metabolismo , Depresión Sináptica a Largo Plazo/fisiología , Neuronas/fisiología , Enfermedad de Parkinson/patología , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Fenómenos Biofísicos , Modelos Animales de Enfermedad , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Proteínas Fluorescentes Verdes/genética , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/genética , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/genética , Neuronas/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatología , Ratas , Ratas Wistar , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D1/deficiencia , Receptores de Dopamina D2/deficiencia , Sustancia P/metabolismo
11.
Brain ; 134(Pt 2): 375-87, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21183486

RESUMEN

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.


Asunto(s)
Cuerpo Estriado/enzimología , Cuerpo Estriado/fisiología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/enzimología , Levodopa/efectos adversos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , GMP Cíclico/farmacología , GMP Cíclico/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Microinyecciones , Neuronas/fisiología , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Inhibidores de Fosfodiesterasa/administración & dosificación , Piperazinas/farmacología , Purinonas/farmacología , Pirimidinonas/farmacología , Ratas , Ratas Wistar
12.
Cell Rep ; 35(11): 109249, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34133916

RESUMEN

Cortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers-due to a defect in precursor cell proliferation during embryogenesis-extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior.


Asunto(s)
Conducta Animal/fisiología , Corteza Cerebral/crecimiento & desarrollo , Interneuronas/patología , Animales , Animales Recién Nacidos , Recuento de Células , Proteínas de Homeodominio/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfohidrolasa PTEN/metabolismo , Parvalbúminas/metabolismo
13.
Cell Rep ; 21(1): 70-83, 2017 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-28978485

RESUMEN

Inhibitory synaptic transmission requires the targeting and stabilization of GABAA receptors (GABAARs) at synapses. The mechanisms responsible remain poorly understood, and roles for transmembrane accessory proteins have not been established. Using molecular, imaging, and electrophysiological approaches, we identify the tetraspanin LHFPL4 as a critical regulator of postsynaptic GABAAR clustering in hippocampal pyramidal neurons. LHFPL4 interacts tightly with GABAAR subunits and is selectively enriched at inhibitory synapses. In LHFPL4 knockout mice, there is a dramatic cell-type-specific reduction in GABAAR and gephyrin clusters and an accumulation of large intracellular gephyrin aggregates in vivo. While GABAARs are still trafficked to the neuronal surface in pyramidal neurons, they are no longer localized at synapses, resulting in a profound loss of fast inhibitory postsynaptic currents. Hippocampal interneuron currents remain unaffected. Our results establish LHFPL4 as a synapse-specific tetraspanin essential for inhibitory synapse function and provide fresh insights into the molecular make-up of inhibitory synapses.


Asunto(s)
Proteínas Portadoras/genética , Potenciales Postsinápticos Inhibidores/fisiología , Proteínas de la Membrana/genética , Subunidades de Proteína/genética , Receptores de GABA-A/genética , Sinapsis/metabolismo , Tetraspaninas/genética , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/metabolismo , Células COS , Proteínas Portadoras/metabolismo , Chlorocebus aethiops , Embrión de Mamíferos , Femenino , Regulación de la Expresión Génica , Interneuronas/citología , Interneuronas/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Técnicas de Placa-Clamp , Agregado de Proteínas , Subunidades de Proteína/metabolismo , Transporte de Proteínas , Células Piramidales/citología , Células Piramidales/metabolismo , Ratas , Receptores de GABA-A/metabolismo , Tetraspaninas/metabolismo , Técnicas de Cultivo de Tejidos
14.
Neuropharmacology ; 101: 341-50, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26471421

RESUMEN

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 µM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 µM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 µM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 µM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 µM) and MK801 (10 µM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.


Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Memantina/farmacología , Sinapsis/efectos de los fármacos , Análisis de Varianza , Animales , Biofisica , Estimulantes del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Picrotoxina/farmacología , Ratas , Ratas Wistar , Factores de Tiempo
15.
Biol Psychiatry ; 77(2): 106-15, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24844602

RESUMEN

BACKGROUND: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease. METHODS: Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. RESULTS: We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. CONCLUSIONS: These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA.


Asunto(s)
Cuerpo Estriado/fisiopatología , Discinesia Inducida por Medicamentos/fisiopatología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Plasticidad Neuronal/fisiología , ras-GRF1/metabolismo , Animales , Antiparkinsonianos/toxicidad , Butadienos/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Levodopa/toxicidad , Ratones Noqueados , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Nitrilos/farmacología , Oxidopamina , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Inhibidores de Proteínas Quinasas/farmacología , Técnicas de Cultivo de Tejidos , ras-GRF1/genética
16.
Sci Rep ; 5: 10933, 2015 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-26190541

RESUMEN

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.


Asunto(s)
Cuerpo Estriado/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteínas de Unión al GTP/genética , Plasticidad Neuronal , Transducción de Señal , Animales , Cuerpo Estriado/efectos de los fármacos , Depresión de Propagación Cortical/genética , Dopamina/metabolismo , Dopamina/farmacología , Femenino , Neuronas GABAérgicas/metabolismo , Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Potenciación a Largo Plazo/genética , Masculino , Ratones , Ratones Noqueados , Actividad Motora , Mutación , Plasticidad Neuronal/genética , ARN Mensajero , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/metabolismo , Factores Sexuales , Transducción de Señal/efectos de los fármacos
17.
Biol Open ; 3(6): 475-85, 2014 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-24812355

RESUMEN

Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.

18.
Exp Neurol ; 261: 320-7, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24858730

RESUMEN

We have analyzed the effects of environmental enrichment (EE) in a seizure-prone mouse model in which the genetic disruption of the presynaptic protein Bassoon leads to structural and functional alterations in the hippocampus and causes early spontaneous seizures mimicking human neurodevelopmental disorders. One-month EE starting at P21 reduced seizure severity, preserved long-term potentiation (LTP) and paired-pulse synaptic responses in the hippocampal CA1 neuronal population and prevented the reduction of spine density and dendrite branching of pyramidal neurons. These data demonstrate that EE exerts its therapeutic effect by normalizing multiple aspects of hippocampal function and provide experimental support for its use in the optimization of existent treatments.


Asunto(s)
Región CA1 Hipocampal/fisiopatología , Ambiente , Epilepsia/patología , Epilepsia/rehabilitación , Potenciación a Largo Plazo/fisiología , Análisis de Varianza , Animales , Animales Recién Nacidos , Biofisica , Modelos Animales de Enfermedad , Estimulación Eléctrica , Epilepsia/genética , Agonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Ratones , Ratones Transgénicos , Mutación/genética , N-Metilaspartato/farmacología , Proteínas del Tejido Nervioso/genética , Neuronas/patología , Técnicas de Placa-Clamp , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología
19.
Exp Neurol ; 261: 377-85, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25058044

RESUMEN

Parkinson's disease (PD) patients exhibit motor and non-motor symptoms that severely affect quality of life. Cognitive alterations in PD subjects have been related to both structural and functional hippocampal changes. Here we investigated the effects of the 6-hydroxydopamine (6-OHDA) lesion in the Medial Forebrain Bundle (MFB) on the hippocampus focusing on the Dentate Gyrus (DG). In vivo microdialysis measurements revealed that the 6-OHDA injection disrupts both dopaminergic and noradrenergic transmission in rat DG. In vitro electrophysiological recordings showed that these neurochemical alterations were accompanied by impairment of long-term depression (LTD) at medial perforant path/DG synapses. Furthermore, this alteration was reversed by l-DOPA treatment. Notably, the therapeutic effect of l-DOPA on LTD was blocked by the antagonism of ß-noradrenergic receptors, but not by dopamine D1 or D2 receptor antagonists. Thus, while the dopaminergic transmission does not seem to be implicated in this therapeutic effect of l-DOPA, the noradrenergic system plays a central role in the synaptic dysfunction of the DG in experimental PD. Our work provides new evidence on the role of catecholamines in DG synaptic plasticity and sheds light on the possible synaptic mechanisms underlying cognitive deficits in PD. Furthermore, our results indicate that l-DOPA exerts a therapeutic effect on the parkinsonian brain through different, coexistent, mechanisms.


Asunto(s)
Antiparkinsonianos/uso terapéutico , Giro Dentado/patología , Levodopa/uso terapéutico , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/patología , Animales , Antiparkinsonianos/farmacología , Benzazepinas/farmacología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Estimulación Eléctrica , Lateralidad Funcional , Levodopa/farmacología , Masculino , Microdiálisis , Norepinefrina/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Wistar , Sulpirida/farmacología
20.
Nat Commun ; 4: 2031, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23774276

RESUMEN

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington's disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor-TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway.


Asunto(s)
Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Globo Pálido/enzimología , Locomoción , Neuronas/enzimología , Receptor trkB/metabolismo , Transducción de Señal , Animales , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Encefalinas/metabolismo , Activación Enzimática/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Marcha/efectos de los fármacos , Eliminación de Gen , Globo Pálido/patología , Globo Pálido/fisiopatología , Proteínas Fluorescentes Verdes/metabolismo , Integrasas/metabolismo , Locomoción/efectos de los fármacos , Ratones , Ratones Noqueados , Ratones Mutantes , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Fosforilación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores de Dopamina D2/metabolismo , Transducción de Señal/efectos de los fármacos , Sinapsis/metabolismo
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