Long-Lasting Visuo-Vestibular Mismatch in Freely-Behaving Mice Reduces the Vestibulo-Ocular Reflex and Leads to Neural Changes in the Direct Vestibular Pathway.

Calibration of the vestibulo-ocular reflex (VOR) depends on the presence of visual feedback. However, the cellular mechanisms associated with VOR modifications at the level of the brainstem remain largely unknown. A new protocol was designed to expose freely behaving mice to a visuo-vestibular mismatch during a 2-week period. This protocol induced a 50% reduction of the VOR. In vivo pharmacological experiments demonstrated that the VOR reduction depends on changes located outside the flocculus/paraflocculus complex. The cellular mechanisms associated with the VOR reduction were then studied in vitro on brainstem slices through a combination of vestibular afferent stimulation and patch-clamp recordings of central vestibular neurons. The evoked synaptic activity demonstrated that the efficacy of the synapses between vestibular afferents and central vestibular neurons was decreased. In addition, a long-term depression protocol failed to further decrease the synapse efficacy, suggesting that the VOR reduction might have occurred through depression-like mechanisms. Analysis of the intrinsic membrane properties of central vestibular neurons revealed that the synaptic changes were supplemented by a decrease in the spontaneous discharge and excitability of a subpopulation of neurons. Our results provide evidence that a long-lasting visuo-vestibular mismatch leads to changes in synaptic transmission and intrinsic properties of central vestibular neurons in the direct VOR pathway. Overall, these results open new avenues for future studies on visual and vestibular interactions conducted in vivo and in vitro.

Dopamine Modulates Motor Control in a Specific Plane Related to Support.

At the acute stage following unilateral labyrinthectomy (UL), rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion) and rolling (utricular lesion). At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats) and systemic injection of apomorphine (APO rats). The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL-rats, exhibited both circling and barrel rolling at the acute stage, and then only circled on the ground. Furthermore, barrel rolling instantaneously reappeared in water in UL rats, which was not the case in 6-OHDA and APO-rats. That is, the lesion of the dopaminergic system on one side did not compromise trim in the pitch and roll planes, even when proprioceptive information related to the basis of support was lacking as in water. Altogether, these results strongly suggest that dopamine does not exert three-dimensional control of the motor system but regulates postural control in one particular plane of space, the one related to the basis of support. In contrast, as previously shown, the vestibular system exerts three-dimensional control on posture. That is, we show here for the first time a relationship between a given neuromodulator and the spatial organization of motor control.

Vestibular integrator neurons have quadratic functions due to voltage dependent conductances.

The nonlinear properties of the dendrites of the prepositus hypoglossi nucleus (PHN) neurons are essential for the operation of the vestibular neural integrator that converts a head velocity signal to one that controls eye position. A novel system of frequency probing, namely quadratic sinusoidal analysis (QSA), was used to decode the intrinsic nonlinear behavior of these neurons under voltage clamp conditions. Voltage clamp currents were measured at harmonic and interactive frequencies using specific nonoverlapping stimulation frequencies. Eigenanalysis of the QSA matrix reduces it to a remarkably compact processing unit, composed of just one or two dominant components (eigenvalues). The QSA matrix of rat PHN neurons provides signatures of the voltage dependent conductances for their particular dendritic and somatic distributions. An important part of the nonlinear response is due to the persistent sodium conductance (gNaP), which is likely to be essential for sustained effects needed for a neural integrator. It was found that responses in the range of 10 mV peak to peak could be well described by quadratic nonlinearities suggesting that effects of higher degree nonlinearities would add only marginal improvement. Therefore, the quadratic response is likely to sufficiently capture most of the nonlinear behavior of neuronal systems except for extremely large synaptic inputs. Thus, neurons have two distinct linear and quadratic functions, which shows that piecewise linear + quadratic analysis is much more complete than just piecewise linear analysis; in addition quadratic analysis can be done at a single holding potential. Furthermore, the nonlinear neuronal responses contain more frequencies over a wider frequency band than the input signal. As a consequence, they convert limited amplitude and bandwidth input signals to wider bandwidth and more complex output responses. Finally, simulations at subthreshold membrane potentials with realistic PHN neuron models suggest that the quadratic functions are fundamentally dominated by active dendritic structures and persistent sodium conductances.

Intrinsic membrane properties of central vestibular neurons in rodents.

Numerous studies in rodents have shown that the functional efficacy of several neurotransmitter receptors and the intrinsic membrane excitability of central vestibular neurons, as well as the organization of synaptic connections within and between vestibular nuclei can be modified during postnatal development, after a lesion of peripheral vestibular organs or in vestibular-deficient mutant animals. This review mainly focuses on the intrinsic membrane properties of neurons of the medial vestibular nuclei of rodents, their postnatal maturation, and changes following experimental or congenital alterations in vestibular inputs. It also presents the concomitant modifications in the distribution of these neurons into different neuron types, which has been based on their membrane properties in relation to their anatomical, biochemical, or functional properties. The main points discussed in this review are that (1) the intrinsic membrane properties can be used to distinguish between two dominant types of neurons, (2) the system remains plastic throughout the whole life of the animal, and finally, (3) the intracellular calcium concentration has a major effect on the intrinsic membrane properties of central vestibular neurons.

Vestibular critical period, maturation of central vestibular neurons, and locomotor control.

Mutant mice are a good model to study to what extent the postnatal activity of sensory afferents is necessary for the maturation of central neurons. In particular, the question arises whether the signals carried by the first-order vestibular neurons, which encode information on the head movement of pups, are necessary for the maturation of second-order vestibular neurons. To address that question, juvenile and adult transgenic, vestibular-deficient mutants where a null mutation of the KCNE1 potassium-channel gene leads to degeneration of all hair cells of the inner ear just after birth were studied. These KCNE1(-/-) mutants are deaf and show quasi-constant head bobbing and a permanent shaker/waltzer phenotype. This behavior is not due to persistent abnormalities of the membrane properties of central vestibular neurons, because their maturation is delayed but not impaired by the absence of sensory vestibular information. On the other hand, the data shed light on how the membrane properties of vestibular neurons might be modified according to functional requirements or following lesions. The expression levels of the protein calretinin that regulates the intracellular free-calcium concentration in central vestibular neurons could play a major role both in intact animals and following labyrinthectomy. By comparing the KCNE1(-/-) mutant mice to other vestibular-deficient animals, it was concluded that the suppression of vestibular inputs during a "critical period" of postnatal development can induce a permanent circling behavior, but that this phenotype is not always due to congenital vestibular deficiency.

Control of neuronal persistent activity by voltage-dependent dendritic properties.

Neural integrators and working memory rely on persistent activity, a widespread neural phenomenon potentially involving persistent sodium conductances. Using a unique combination of voltage-clamp, dynamic-clamp, and frequency-domain techniques, we have investigated the role of voltage-dependent conductances on the dendritic electrotonic structure of neurons of the prepositus hypoglossi nucleus (PHN), which is known to be involved in oculomotor integration. The PHN contains two main neuronal populations: type B neurons with a double afterhyperpolarization and type D neurons, which not only are oscillatory but also have a greater electrotonic length than that of type B neurons. The persistent sodium conductance is present in all PHN neurons, although its effect on the dynamic electrotonic structure is shown to significantly differ in the two major cell types present in the nucleus. The electrotonic differences are such that the persistent sodium conductance can be almost perfectly manipulated in a type B neuron using an on-line dynamic clamp to add or subtract virtual sodium ion channels. The dynamic-clamp results are confirmed by data-fitted models, which suggest that the persistent sodium conductance has two different roles depending on its somatic versus dendritic location: perisomatic conductances could play a major role in maintaining action potential discharge and dendritic conductances would be more involved in other computational properties, such as those involving remote synaptic processing or bistable events.

Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channels.

Small-conductance Ca(2+)-activated potassium (SK) channels are heteromeric complexes of SK alpha-subunits and calmodulin that modulate membrane excitability, are responsible for part of the after-hyperpolarization (AHP) following action potentials, and thus control the firing patterns and excitability of most central neurons. An engineered knockout allele for the SK2 subunit has previously been reported. The hippocampal neurons of these mice lacked the medium latency component of the AHP, but the animals were not described as presenting any overt behavioral phenotype. In this report, we describe a deletion in the 5' region of the Kcnn2 gene encoding the SK2 subunit in the mouse neurological frissonnant (fri) mutant. The frissonnant mutant phenotype is characterized by constant rapid tremor and locomotor instability. It has been suggested, based merely on its phenotype, as a potential model for human Parkinson disease. We used a positional cloning strategy to identify the mutation underlying the frissonnant phenotype. We narrowed the genetic disease interval and identified a 3,441-bp deletion in the Kcnn2 gene, one of the three candidate genes present in the interval. Expression studies showed complete absence of normal Kcnn2 transcripts while some tissue-specific abnormal truncated variants were detected. Intracellular electrophysiological recordings of central vestibular neurons revealed permanent alterations of the AHP and firing behavior that might cause the tremor and associated locomotor deficits. Thus, the fri mutation suggests a new, potentially important physiological role, which had not been described, for the SK2 subunit of small-conductance Ca(2+)-activated potassium channels.

Furosemide modulation of GABA(A) receptors in dopaminergic neurones of the rat substantia nigra.

Furosemide is a diuretic which has been shown to decrease recombinant GABA(A) receptor (GABA(A)R)-mediated currents and also to block epileptiform discharges. Here, we show that furosemide actions on GABA(A)Rs of rat substantia nigra dopaminergic neurones depend on both furosemide and GABA(A)R agonist concentrations. The whole-cell currents induced by low concentrations of GABA (5 microM) or by the selective GABA(A)R agonist isoguvacine (7-25 microM) were enhanced by 200 microM furosemide. However, furosemide did not affect GABA(A)R currents induced by 60 microM isoguvacine and even decreased those induced by 200 microM isoguvacine. At the single-channel level, furosemide had comparable effects. It increased the open time proportion with 7 microM isoguvacine but had no significant effect on the open time proportion with 60 microM isoguvacine. These effects resulted from a differential action on the multiple conductance levels activated by GABA(A)R agonists. The concentration-response relationship to isoguvacine in the whole-cell mode revealed the presence of a high and a low apparent affinity GABA(A)R population (EC(50) 4.8 vs 89 microM). These two populations of receptors coexist in the same dopaminergic neurone. They are both furosemide-sensitive and may represent different GABA(A)R subunit assemblies.