Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence

International audienceThe spontaneous activity pattern of adult dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) results from interactions between intrinsic membrane conductances and afferent inputs. In adult SNc DA neurons, low-frequency tonic background activity is generated by intrinsic pacemaker mechanisms, whereas burst generation depends on intact synaptic inputs in particular the glutamatergic ones. Tonic DA release in the striatum during pacemaking is required to maintain motor activity, and burst firing evokes phasic DA release, necessary for cue-dependent learning tasks. However, it is still unknown how the firing properties of SNc DA neurons mature during postnatal development before reaching the adult state. We studied the postnatal developmental profile of spontaneous and evoked AMPA and NMDA (N-Methyl-D-aspartic acid) receptor-mediated excitatory postsynaptic currents (EPSCs) in SNc DA neurons in brain slices from immature (postnatal days P4-P10) and young adult (P30-P50) tyrosine hydroxylase (TH)-green fluorescent protein mice. We found that somato-dendritic fields of SNc DA neurons are already mature at P4-P10. In contrast, spontaneous glutamatergic EPSCs show a developmental sequence. Spontaneous NMDA EPSCs in particular are larger and more frequent in immature SNc DA neurons than in young adult ones and have a bursty pattern. They are mediated by GluN2B and GluN2D subunit-containing NMDA receptors. The latter generate long-lasting, DQP 1105-sensitive, spontaneous EPSCs, which are transiently recorded during this early period. Due to high NMDA activity, immature SNc DA neurons generate large and long lasting NMDA receptor-dependent (APV-sensitive) bursts in response to the stimulation of the subthalamic nucleus. We conclude that the transient high NMDA activity allows calcium influx into the dendrites of developing SNc DA neurons

A Cellular Mechanism for the Transformation of a Sensory Input into a Motor Command

International audienceThe initiation and control of locomotion largely depend on processing of sensory inputs. The cellular bases of locomotion have been extensively studied in lampreys where reticulospinal (RS) neurons constitute the main descending system activating and controlling the spinal locomotor networks. Ca 2ϩ imaging and intracellular recordings were used to study the pattern of activation of RS neurons in response to cutaneous stimulation. Pressure applied to the skin evoked a linear input/output relationship in RS neurons until a threshold level, at which a depolarizing plateau was induced, the occurrence of which was associated with the onset of swimming activity in a semi-intact preparation. The occurrence of a depolarizing plateau was abolished by blocking the NMDA receptors that are located on RS cells. Moreover, the depolarizing plateaus were accompanied by a rise in [Ca 2ϩ ] i , and an intracellular injection of the Ca 2ϩ chelator BAPTA into single RS cells abolished the plateaus, suggesting that the latter are Ca 2ϩ dependent and rely on intrinsic properties of RS cells. The plateaus were shown to result from the activation of a Ca 2ϩ-activated nonselective cation current that maintains the cell in a depolarized state. It is concluded that this intrinsic property of the RS neuron is then responsible for the transformation of an incoming sensory signal into a motor command that is then forwarded to the spinal locomotor networks

Mature dentate granule cells show different intrinsic properties depending on the behavioral context of their activation

The dentate gyrus (DG) plays a crucial role in learning, memory and spatial navigation. Only a small fraction of mature dentate granule cells (mDGCs) is active during behavior, while the large majority remains silent. To date, the properties of this active subset of neurons remain poorly investigated. Using fosGFP transgenic mice, we show ex vivo that activated mDGCs, from mice maintained in their home cage, exhibit a marked lower intrinsic excitability compared to the non-activated cells. Remarkably, activated mDGCs, from mice trained in a virtual environment, are more excitable than those from mice maintained in their home cage. Therefore, we show that activated mDGCs display different intrinsic properties and excitable states depending on the context of their activation. We propose that these properties could constitute a neural signature of cell assemblies recruited in different behavioral contexts

Perinatal Development of the Motor Systems Involved in Postural Control

Motor behaviors of some species, such as the rat and the human baby, are quite immature at birth. Here we review recent data on some of the mechanisms underlying the postnatal maturation of posture in the rat, in particular the development of pathways descending from the brain stem and projecting onto the lumbar enlargement of the spinal cord. A short-lasting depletion in serotonin affects both posture and the excitability of motoneurons. Here we try to extrapolate to human development and suggest that the abnormalities in motor control observed in childhood—e.g, deficits in motor coordination—might have their roots in the prenatal period, in particular serotonin depletion due to exposure to several environmental and toxicological factors during pregnancy

Serotonin enhances the resistance reflex of the locomotor network of the crayfish through multiple modulatory effects that act cooperatively.

International audienceSerotonin (5HT) is an endogenous amine that modifies posture in crustacea. Here, we examined the mechanisms of action of 5HT on the resistance reflex in crayfish legs. This reflex, which counteracts movements imposed on a limb, is based on a negative feedback system formed by proprioceptors that sense joint angle movements and activate opposing motoneurons. We performed intracellular recordings from depressor motoneurons while repetitively stretching and releasing a leg joint proprioceptor in a resting in vitro preparation (i.e., a preparation that lacks spontaneous rhythmic activity). 5HT increased the amplitude of the depolarization during the release phase of the proprioceptor (corresponding to an upward movement of the leg) and the discharge frequency of the motoneurons. The 5HT-induced increase in the resistance reflex is caused, to a large extent, by polysynaptic pathways because it was very attenuated in the presence of high divalent cation solution. In addition to this activation of the polysynaptic pathways, 5HT also has postsynaptic effects that enhance the resistance reflex. 5HT causes a tonic depolarization, as well as an increase in the time constant and input resistance of motoneurons. We developed a simple mathematical model to describe the integrative properties of the motoneurons. The conclusion of this study is that the input frequency and the decay time constant of the EPSPs interact in such a way that small simultaneous changes in these parameters can cause a large effect on summation. Therefore, the conjunction of presynaptic and postsynaptic changes produces a strong cooperative effect on the resistance reflex response

The in vitro neonatal spinal cord preparation : A new insight into mammalian locomotor mechanisms.

International audienc

Abnormal Development of Glutamatergic Synapses Afferent to Dopaminergic Neurons of the Pink1−/− Mouse Model of Parkinson’s Disease

International audienceIn a preceding study, we showed that in adult pink1−/− mice, a monogenic animal model of Parkinson’s disease (PD), striatal neurons display aberrant electrical activities that precede the onset of overt clinical manifestations. Here, we tested the hypothesis that the maturation of dopaminergic (DA) neurons of the pink1−/− substantia nigra compacta (SNc) follows, from early stages on, a different developmental trajectory from age-matched wild type (wt) SNc DA neurons. We used immature (postnatal days P2–P10) and young adult (P30–P90) midbrain slices of pink1−/− mice expressing the green fluorescent protein in tyrosine hydroxylase (TH)-positive neurons. We report that the developmental sequence of N-Methyl-D-aspartic acid (NMDA) spontaneous excitatory postsynaptic currents (sEPSCs) is altered in pink1−/− SNc DA neurons, starting from shortly after birth. They lack the transient episode of high NMDA receptor-mediated neuronal activity characteristic of the immature stage of wt SNc DA neurons. The maturation of the membrane resistance of pink1−/− SNc DA neurons is also altered. Collectively, these observations suggest that electrical manifestations occurring shortly after birth in SNc DA neurons might lead to dysfunction in dopamine release and constitute an early pathogenic mechanism of PD

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin (PV) and somatostatin (SST) neurons, two major classes of GABAergic neurons in the hippocampus. We show that 4.1B-deficiency induces disruption of juxtaparanodal K + channel clustering and mislocalization of nodal or heminodal Na + channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens SST cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking PV cells do not appear affected. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons

Abstract The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K + channel clustering and mislocalization of nodal or heminodal Na + channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory