RESUMEN
Different types of sensory neurons in the dorsal root ganglia project axons to the spinal cord to convey peripheral information to the central nervous system. Whereas most proprioceptive axons enter the spinal cord medially, cutaneous axons typically do so laterally. Because heavily myelinated proprioceptive axons project to the ventral spinal cord, proprioceptive axons and their associated oligodendrocytes avoid the superficial dorsal horn. However, it remains unclear whether their exclusion from the superficial dorsal horn is an important aspect of neural circuitry. Here we show that a mouse null mutation of Sema6d results in ectopic placement of the shafts of proprioceptive axons and their associated oligodendrocytes in the superficial dorsal horn, disrupting its synaptic organization. Anatomical and electrophysiological analyses show that proper axon positioning does not seem to be required for sensory afferent connectivity with motor neurons. Furthermore, ablation of oligodendrocytes from Sema6d mutants reveals that ectopic oligodendrocytes, but not proprioceptive axons, inhibit synapse formation in Sema6d mutants. Our findings provide new insights into the relationship between oligodendrocytes and synapse formation in vivo, which might be an important element in controlling the development of neural wiring in the central nervous system.
Asunto(s)
Coristoma/genética , Oligodendroglía , Semaforinas/genética , Enfermedades de la Médula Espinal/genética , Sinapsis/genética , Animales , Animales Modificados Genéticamente , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Ratones , Modelos Biológicos , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/patología , Neurogénesis/genética , Neurogénesis/fisiología , Propiocepción/genética , Semaforinas/fisiología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/patología , Transducción de Señal/genética , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/patología , Enfermedades de la Médula Espinal/metabolismo , Enfermedades de la Médula Espinal/patología , Sinapsis/metabolismo , Sinapsis/patología , Transmisión Sináptica/genética , Transmisión Sináptica/fisiologíaRESUMEN
The effects of a GABAB agonist, baclofen, on mechanical noxious and innocuous synaptic transmission in the substantia gelatinosa (SG) were investigated in adult rats with the in vivo patch-clamp technique. Under current-clamp conditions, perfusion with baclofen (10 µm) on the surface of the spinal cord caused hyperpolarisation of SG neurons and a decrease in the number of action potentials elicited by pinch and touch stimuli applied to the receptive field of the ipsilateral hindlimb. The suppression of action potentials was preserved under blockade of postsynaptic G-proteins, although baclofen-induced hyperpolarisation was completely blocked. These findings suggest presynaptic effects of baclofen on the induced action potentials. Under voltage-clamp conditions, application of baclofen reduced the frequency, but not the amplitude, of miniature excitatory postsynaptic currents (mEPSCs), whereas the GABAB receptor antagonist CGP55845 increased the frequency of mEPSCs without affecting the amplitude. Furthermore, application of a GABA uptake inhibitor, nipecotic acid, decreased the frequency of mEPSCs; this effect was blocked by CGP55845, but not by the GABAA antagonist bicuculline. Both the frequency and the amplitude of the pinch-evoked barrage of excitatory postsynaptic currents (EPSCs) were suppressed by baclofen in a dose-dependent manner. The frequency and amplitude of touch-evoked EPSCs was also suppressed by baclofen, but the suppression was significantly smaller than that of pinch-evoked EPSCs. We conclude that mechanical noxious transmission is presynaptically blocked through GABAB receptors in the SG, and is more effectively suppressed than innocuous transmission, which may account for a part of the mechanism of the efficient analgesic effects of baclofen.
Asunto(s)
Baclofeno/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Factores de Edad , Animales , Potenciales Postsinápticos Excitadores/fisiología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Masculino , Dimensión del Dolor/métodos , Técnicas de Placa-Clamp/métodos , Estimulación Física/efectos adversos , Células del Asta Posterior/fisiología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/fisiología , Resultado del TratamientoRESUMEN
In mammalian spinal cord, group Ia proprioceptive afferents form selective monosynaptic connections with a select group of motor pool targets. The extent to which sensory recognition of motor neurons contributes to the selectivity of sensory-motor connections remains unclear. We show here that proprioceptive sensory afferents that express PlexinD1 avoid forming monosynaptic connections with neurons in Sema3E(+) motor pools yet are able to form direct connections with neurons in Sema3E(off) motor pools. Anatomical and electrophysiological analysis of mice in which Sema3E-PlexinD1 signaling has been deregulated or inactivated genetically reveals that repellent signaling underlies aspects of the specificity of monosynaptic sensory-motor connectivity in these reflex arcs. A semaphorin-based system of motor neuron recognition and repulsion therefore contributes to the formation of specific sensory-motor connections in mammalian spinal cord.