A novel short-term plasticity of intrinsic excitability in the hippocampal CA1 pyramidal cells.

Changes in neuronal activity often trigger compensatory mechanisms aimed at regulating network activity homeostatically. Here we have identified and characterized a novel form of compensatory short-term plasticity of membrane excitability, which develops early after the eye-opening period in rats (P16-19 days) but not before that developmental stage (P9-12 days old). Holding the membrane potential of CA1 neurons right below the firing threshold from 15 s to several minutes induced a potentiation of the repolarizing phase of the action potentials that contributed to a decrease in the firing rate of CA1 pyramidal neurons in vitro. Furthermore, the mechanism for inducing this plasticity required the action of intracellular Ca(2+) entering through T-type Ca(2+) channels. This increase in Ca(2+) subsequently activated the Ca(2+) sensor K(+) channel interacting protein 3, which led to the increase of an A-type K(+) current. These results suggest that Ca(2+) modulation of somatic A-current represents a new form of homeostatic regulation that provides CA1 pyramidal neurons with the ability to preserve their firing abilities in response to membrane potential variations on a scale from tens of seconds to several minutes.

Intrinsic excitability is altered by hypothyroidism in the developing hippocampal CA1 pyramidal cells.

Thyroid hormone plays an essential role in brain development, so its deficiency during a critical developmental period has been associated with profound neurological deficits, including irreversible mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the postnatal development of membrane excitability of CA1 hippocampal pyramidal cells. Current clamp recordings in the whole cell patch clamp configuration showed that the action potential of cells from hypothyroid animals presented shorter width, slower depolarization, and faster repolarization rates compared with controls both in early postnatal and pre-weanling ages. Additionally, thyroid hormone deficiency reduced the intrinsic membrane excitability as measured by the reduced number of evoked action potentials for a given depolarizing slope and by the more depolarized firing threshold observed in hypothyroid animals. Then we analyzed the fast-repolarizing A- and D-type potassium currents, as they constitute one of the major factors underlying intrinsic membrane excitability. Hypothyroid rats showed increased A-current density and a reduced isolated I(D)-like current, accompanied by parallel changes in the expression of the channels responsible for these currents in the CA1 region: Kv4.2, Kv4.3, and Kv1.2. Therefore, we suggest that the increased A-current density, subsequent to an increment in its channel expression, together with the decrease of Na(+)-currents, might help explain the functional alterations in the neuronal discharge, in the firing threshold, and in the action potential repolarization of hypothyroid pyramidal neurons.

Role of low-voltage-activated calcium current on the firing pattern alterations induced by hypothyroidism in the rat hippocampus.

Thyroid hormone deficiency during a critical period of development severely affects cognitive functions, resulting in profound mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the development of the intrinsic properties of CA1 hippocampal pyramidal cells. These cells are known to exhibit different firing patterns during development, being classified as either regular-spiking or burst-spiking cells. Patch-clamp experiments showed that hypothyroid rats presented a larger number of regular-spiking cells at early postnatal age (P9-11). This difference in firing-pattern distribution disappeared at the pre-weanling age (P17-19), when almost every cell displayed bursting behavior in both control and hypothyroid rats. However, when studied in detail, weanling hypothyroid rats presented a smaller number of spikes per burst than did control animals. One of the major factors behind bursting behavior is sustained depolarization following an action potential. In this study, we show that action potential afterdepolarizations of hypothyroid animals registered shorter half-durations than did controls, a fact which could explain the smaller number of action potentials per burst. Additionally, the afterdepolarizations observed on both hypothyroid and control neurons were highly sensitive to low concentrations of nickel, suggesting that a low-threshold Ca(2+) current is key in the generation of spike afterdepolarizations and in the control of the bursting pattern of firing of these neurons. In agreement with this, experiments performed on dissociated hippocampal neurons have shown that this current is significantly depressed in hypothyroid animals. Therefore, we conclude that an alteration of the low-threshold calcium current is the basic factor explaining the differences observed in the firing behavior of hypothyroid animals.

Sensitivity to glutamate neurotoxicity in different developmental periods of the rat cochlea.

Cochlear neurotoxicity induced by the intraperitoneal administration of monosodium glutamate (MSG) has been analyzed during the postnatal development of the auditory receptor of the rat. The animals were treated with MSG during two postnatal periods. The electrophysiological recordings showed that MSG treatment produced a decrease in the 8th nerve compound action potential. The effect was more marked in the animals treated between the 9th and 12th postnatal day than in the others, with a qualitative decrease in neuronal density in the spiral ganglion. These results suggest that there is a period of maximum sensitivity to the cochlear neurotoxicity induced by MSG in the postnatal development of the rat.

Changes in the cochlear dopaminergic system of the aged rat.

The levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) have been quantified in cochleae of male and female rats aged 3, 6, 9, 12, 19 and 24 months. Animals were exposed for 1 h, under general anesthesia, to: (1) silence (basal conditions) or (2) white noise at 90 dB SPL. Afterwards, the concentrations of DA, DOPAC and HVA were determined by HPLC with electrochemical detection in homogenates of individual cochleae. In basal conditions, the cochlear concentrations of DA, DOPAC and HVA in aged females were higher than in adult ones. The concentrations of DA and DOPAC were also higher in aged males with respect to adult ones. A decrease in DA and an increase in DOPAC and HVA concentrations, with respect to silence, were detected when adult animals were exposed to noise. Meanwhile, aged animals showed either a noise-induced increase or no modification of DA and DOPAC with respect to basal levels. Present results suggest age-related failures in DA release and metabolizing mechanisms within the cochlea, together with a compensatory DA synthesis increase. However, the possibility of an initial damage in the primary auditory neurons which could also stimulate the synthesis of DA must not be excluded. Present age-related changes could indicate that the cochlear dopaminergic innervation is affected during the aging process. Since this innervation plays an important role in both the modulation and the protection of the primary auditory neurons, its metabolic alteration could profoundly modify the auditory process.

Noise stimulation decreases the concentration of norepinephrine in the rat cochlea.

The present study was designed to analyze, by using high performance liquid chromatography (HPLC), the effect of acoustic stimulation on the cochlear concentration of norepinephrine (NE). Independently of the rat strain (Long-Evans or Wistar strains), NE concentration decreased about 18% when animals were exposed to white noise (90 dB SPL for 1 h). The same decrease was observed in animals perfused by aortic pathway to remove the blood, indicating that this decrease corresponds exclusively to a neurophysiological process. In fact, these findings could indicate that noise stimulation is involved in the NE release from sympathetic fibers innervating the cochlea. This likely release of NE supports that sympathetic fibers play a functional role in cochleae exposed to noisy situations.

Effect of superior cervical ganglionectomy on catecholamine concentration in rat cochlea.

Both noradrenergic and dopaminergic nerve terminals have been described in the cochlea. The present report focused on the effect of superior cervical ganglionectomy (SCGx) on monoamine concentration in adult rat cochlea. In homogenates of whole cochleas, we measured the concentrations of norepinephrine (NE), dopamine (DA) and its main metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), by HPLC coupled to electrochemical detection. Measurements were carried out 4 h, 24 h or 6 days after unilateral SCGx. Most of the NE (approximately 82%) was lost after sympathectomy on the ipsilateral side, indicating that the principal localization of cochlear NE is in peripheral sympathetic fibers. Since about 18% of NE remained detectable 6 days after SCGx, a second origin of cochlear noradrenergic fibers may exist. Cochlear concentrations of DA or its metabolites did not change after SCGx. Therefore, DA and NE are located in two different populations of fibers within the cochlea, and are presumably related to distinct functional roles.

Effects of acute and chronic administration of cyclosporine on dopamine metabolism in the rat cochlea.

The effect of cyclosporine (CyA) on dopamine (DA) metabolism at the cochlear level was analyzed. Adult male rats were submitted to CyA treatment at the doses of 1, 5 or 20 mg/Kg/day, for 1 day (acute) or 8 days (chronic). Cochlear contents of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by using high performance liquid chromatography (HPLC-ED). Either dose of acutely administered CyA did not modify cochlear DA content and markedly reduced that of DOPAC, in a non dose-dependent way. Acute administration of 5 mg/Kg of CyA decreased HVA content while the highest dose increased it. DOPAC/DA index was significantly reduced with either CyA dose, although HVA/DA index was not modified. Chronic treatment with CyA markedly reduced cochlear DA and DOPAC contents in a non dose-dependent way. However, HVA content decreased after the highest administration dose of the drug. DOPAC/DA index was further reduced after the drug chronic administration. An increased HVA/DA index was surprisingly observed, after chronic administration of either dose of the drug, the response being dose- dependent. These data show that acute treatment with CyA mainly affects the DA reuptake, while chronic treatment affected both DA reuptake and metabolism at the cochlear level.

Presence of catecholamines and serotonin in the rat vestibule.

The concentrations of norepinephrine (NE), dopamine (DA) and its metabolites DOPAC and HVA, and serotonin (5-HT) and its metabolite 5-HIAA, were quantified in the rat vestibule. For this purpose, homogenates of vestibules, of albino and pigmented rats, were analyzed using HPLC with electrochemical detection. Vestibules of pigmented rats showed higher DOPAC and HVA concentrations than those of albino rats, and male pigmented rats also showed significantly more DA than male albino rats. These results could indicate that the rate of DA metabolism in vestibules was higher in pigmented than in albino rats. The vestibular concentrations of NE and 5-HT did not differ significantly between the two strains. In contrast, 5-HIAA concentration was higher in vestibules of pigmented rats than in those of albino rats, suggesting an increased 5-HT metabolism for the former strain. Differences in monoamine concentrations between the two sexes o the same strain were scarce. Only, a higher HVA concentration in vestibules of females could indicate a higher DA metabolism.

Serotonergic innervation of the organ of Corti of the cat cochlea.

The presence and distribution of serotonin-containing fibers within the adult cat cochlea is reported here for the first time. The 5-HT-like immunoreactive fibers were mainly found in the middle coils of the cat cochlea, following a peripheral distribution similar to that of the olivocochlear lateral efferent system (OLES). Thus, 5-HT-like immunoreactive varicose fibers were found within the intraganglionic spiral bundle, the inner and the tunnel bundles, although, some variation with the distribution of other neuroactive substances of the OLES were observed. In particular, some isolated fibers from the tunnel bundle branched towards the first row of the outer hair cells. Cochlear serotonergic fibers might be involved in the auditory processing within the cochlea as efferent modulating fibers.

Piribedil affects dopamine turnover in cochleas stimulated by white noise.

The presence of dopamine (DA) within the cochlea has been previously reported, indicating that its turnover increases under noise stimulation. In the present report, piribedil, a dopaminergic D2 agonist, was used in order to provide evidence of the activity of D2 receptors in the turnover of DA under noise stimulation. Long-Evans rats were intraperitoneally injected with distilled water or with a solution of piribedil one hour previously to either noise or silence exposure. Noise stimulation was performed in an anechoic chamber at 70, 90 or 110 dB SPL for one hour. The animals were then sacrificed and the cochlear contents of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were quantified by HPLC with electrochemical detection. The administration of piribedil to animals kept in silence did not modify the cochlear DA, DOPAC and HVA content. Noise stimulation resulted in a decrease of the cochlear DA content and an increase of the cochlear DOPAC and HVA contents in vehicle treated animals. The administration of piribedil resulted in a blockade of this noise induced cochlear DA turnover. These results suggest that piribedil stimulates cochlear D2 receptors controlling the cochlear DA release. Piribedil action on D2 receptors could explain the improvement observed in some cochleo-vestibular diseases signs after piribedil treatment.

Piribedil could modify dopamine turnover in cochleas under noise stimulation.

Dopamine (DA) is one of the putative neurotransmitters of the lateral efferent olivocochlear fibers. The cochlear DA content after noise exposure was analyzed using high-performance liquid chromatography coupled with electrochemical detection. Animals were exposed for 1 h to white noise at 70, 90 or 110 dB SPL or were kept in conditions of silence. Half of the animals were pretreated with piribedil, a D2 agonist, and the other half served as controls. In control (untreated) animals, noise stimulation resulted in a progressive decrease of cochlear DA concentration. This decrease was scarcely detected when animals were pretreated with piribedil. Present findings indicate that piribedil modifies cochlear DA turnover under noise stimulation.

Effects of noise stimulation on cochlear dopamine metabolism.

Dopamine (DA) appears to be one of the putative neurotransmitters of the lateral efferent olivocochlear fibers. However, its role in the cochlear physiology remains unknown. In this study, animals were exposed for 1 h to white noise at 70, 90 or 110 dB SPL or were kept in silence conditions. Afterwards, the cochlear content of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were analyzed using HPLC coupled to electrochemical detection. Cochlear DA concentration decreased with the noise intensity, while cochlear DOPAC and HVA concentrations increased. Males presented higher cochlear DOPAC contents and lower HVA contents than females. This sexual dimorphism could be related to the link between DA and gonadal steroids. Present results show that DA, as other lateral efferent neurotransmitters, is released and metabolized in relationship with the noise stimulation, and suggest that DA could be involved in the modulation of the type I afferent fiber activity.