RESUMEN
Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Ataxia/fisiopatología , Canalopatías/fisiopatología , Canal de Potasio Kv.1.1/metabolismo , Miocimia/fisiopatología , Células de Purkinje/metabolismo , Animales , Ataxia/genética , Ataxia/metabolismo , Calcio/metabolismo , Canalopatías/genética , Canalopatías/metabolismo , Modelos Animales de Enfermedad , Venenos Elapídicos/farmacología , Femenino , Expresión Génica , Canal de Potasio Kv.1.1/antagonistas & inhibidores , Canal de Potasio Kv.1.1/genética , Ratones , Ratones Transgénicos , Microtomía , Mutación , Miocimia/genética , Miocimia/metabolismo , Técnicas de Placa-Clamp , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Terminales Presinápticos/patología , Células de Purkinje/efectos de los fármacos , Células de Purkinje/patología , Transmisión Sináptica/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Until recently, the study of plasticity of neural circuits focused almost exclusively on potentiation and depression at excitatory synapses on principal cells. Other elements in the neural circuitry, such as inhibitory synapses on principal cells and the synapses recruiting interneurons, were assumed to be relatively inflexible, as befits a role of inhibition in maintaining stable levels and accurate timing of neuronal activity. It is now evident that inhibition is highly plastic, with multiple underlying cellular mechanisms. This Review considers these recent developments, focusing mainly on functional and structural changes in GABAergic inhibition of principal cells and long-term plasticity of glutamateric recruitment of inhibitory interneurons in the mammalian forebrain. A major challenge is to identify the adaptive roles of these different forms of plasticity, taking into account the roles of inhibition in the regulation of excitability, generation of population oscillations, and precise timing of neuronal firing.
Asunto(s)
Neuronas GABAérgicas/fisiología , Red Nerviosa/fisiología , Inhibición Neural/fisiología , Plasticidad Neuronal , Animales , Modelos Biológicos , Red Nerviosa/citologíaRESUMEN
In the central nervous system, electrical signals passing along nerve cells are speeded by cells called oligodendrocytes, which wrap the nerve cells with a fatty layer called myelin. This layer is important for rapid information processing, and is often lost in disease, causing mental or physical impairment in multiple sclerosis, stroke, cerebral palsy and spinal cord injury. The myelin speeds the information flow in two ways, by decreasing the capacitance of the nerve cell and by increasing its membrane resistance, but little is known about the latter aspect of myelin function. By recording electrically from oligodendrocytes and imaging their morphology we characterised the geometry and, for the first time, the resistance of myelin in the brain. This revealed differences between the properties of oligodendrocytes in two brain areas and established that the resistance of myelin is sufficiently high to prevent significant slowing of the nerve electrical signal by current leakage through the myelin.
Asunto(s)
Cerebelo/fisiología , Cuerpo Calloso/fisiología , Fenómenos Electrofisiológicos/fisiología , Oligodendroglía/citología , Oligodendroglía/fisiología , Potenciales de Acción/fisiología , Animales , Axones/fisiología , Cerebelo/citología , Simulación por Computador , Cuerpo Calloso/citología , Capacidad Eléctrica , Impedancia Eléctrica , Sinapsis Eléctricas/fisiología , Modelos Neurológicos , Vaina de Mielina/fisiología , Fibras Nerviosas Mielínicas/fisiología , Neuronas/citología , Neuronas/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
Oligodendrocyte precursor cells (OPCs) have become the focus of intense research, not only because they generate myelin-forming oligodendrocytes in the normal CNS, but because they may be suitable for transplantation to treat disorders in which myelin does not form or is damaged, and because they have stem-cell-like properties in that they can generate astrocytes and neurons as well as oligodendrocytes. In this article we review the electrical signalling properties of OPCs, including the synaptic inputs they receive and their use of voltage-gated channels to generate action potentials, and we describe experiments attempting to detect output signalling from OPCs. We discuss controversy over the existence of different classes of OPC with different electrical signalling properties, and speculate on the lineage relationship and myelination potential of these different classes of OPC. Finally, we point out that, since OPCs are the main proliferating cell type in the mature brain, the discovery that they can develop into neurons raises the question of whether more neurons are generated in the mature brain from the classical sites of neurogenesis in the subventricular zone of the lateral ventricle and the hippocampal dentate gyrus or from the far more widely distributed OPCs.
Asunto(s)
Potenciales de Acción/fisiología , Sistema Nervioso Central/fisiología , Oligodendroglía/fisiología , Células Madre/fisiología , Transmisión Sináptica/fisiología , Animales , Antígenos/metabolismo , Comunicación Celular/fisiología , Sistema Nervioso Central/citología , Humanos , Activación del Canal Iónico/fisiología , Vaina de Mielina/metabolismo , Neurogénesis/fisiología , Oligodendroglía/citología , Proteoglicanos/metabolismo , Células Madre/citologíaRESUMEN
A defining feature of glial cells has been their inability to generate action potentials. We show here that there are two distinct types of morphologically identical oligodendrocyte precursor glial cells (OPCs) in situ in rat CNS white matter. One type expresses voltage-gated sodium and potassium channels, generates action potentials when depolarized and senses its environment by receiving excitatory and inhibitory synaptic input from axons. The other type lacks action potentials and synaptic input. We found that when OPCs suffered glutamate-mediated damage, as occurs in cerebral palsy, stroke and spinal cord injury, the action potential-generating OPCs were preferentially damaged, as they expressed more glutamate receptors, and received increased spontaneous glutamatergic synaptic input in ischemia. These data challenge the idea that only neurons generate action potentials in the CNS and imply that the development of therapies for demyelinating disorders will require defining which OPC type can carry out remyelination.
Asunto(s)
Potenciales de Acción/fisiología , Comunicación Celular/fisiología , Fibras Nerviosas Mielínicas/metabolismo , Oligodendroglía/clasificación , Transmisión Sináptica/fisiología , Animales , Antígenos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Glutamatos/farmacología , Técnicas In Vitro , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos , Oligodendroglía/metabolismo , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/metabolismo , Proteoglicanos/metabolismo , Ratas , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Canales de Sodio/metabolismo , Células Madre/citología , Células Madre/metabolismoRESUMEN
Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100 microM) and BaCl(2) (300 microM) (fEPSP=78.9+/-5.4% of baseline 58-60 min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10 microM), and with the protein kinase A (PKA) inhibitor KT5720 (1 microM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200 nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1 microM) or L-type Ca(2+) channels with nimodipine (1 microM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.
Asunto(s)
Canales de Calcio Tipo P/fisiología , Moduladores de Receptores de Cannabinoides/metabolismo , AMP Cíclico/metabolismo , Endocannabinoides , Depresión Sináptica a Largo Plazo/fisiología , Núcleo Accumbens/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Compuestos de Bario/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Moduladores de Receptores de Cannabinoides/antagonistas & inhibidores , Carbazoles/farmacología , Cloruros/farmacología , Colforsina/farmacología , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Indoles/farmacología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Bloqueadores de los Canales de Potasio/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors.
Asunto(s)
Isquemia Encefálica/patología , Sistema Nervioso Central/patología , Antagonistas de Aminoácidos Excitadores/farmacología , Oligodendroglía/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Isquemia Encefálica/tratamiento farmacológico , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Agonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Memantina/farmacología , Proteína Básica de Mielina/metabolismo , N-Metilaspartato/farmacología , Técnicas de Placa-Clamp/métodos , Unión Proteica/efectos de los fármacos , Ratas , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
BACKGROUND: Cannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses. CONCLUSIONS/SIGNIFICANCE: Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.