Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences

International audienceParkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopa-mine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation

A new class of scorpion toxin binding sites related to an A-type K+ channel: pharmacological characterization and localization in rat brain

AbstractA new scorpion toxin (3751.8 Da) was isolated from the Buthus martensi venom, sequenced and chemically synthesized (sBmTX3). The A-type current of striatum neurons in culture completely disappeared when 1 μM sBmTX3 was applied (Kd=54 nM), whereas the sustained K+ current was unaffected. 125I-sBmTX3 specifically bound to rat brain synaptosomes (maximum binding=14 fmol mg−1 of protein, Kd=0.21 nM). A panel of toxins yet described as specific ligands for K+ channels were unable to compete with 125I-sBmTX3. A high density of 125I-sBmTX3 binding sites was found in the striatum, hippocampus, superior colliculus, and cerebellum in the adult rat brain

Rôle des canaux Kv1.1 et Kv1.3 au cours des processus mnésiques chez le rat

Les expériences rapportées dans ce mémoire avaient pour but d'étudier le rôle des canaux KV1.1 et KV1.3 au cours des processus d'apprentissage et de mémoire. Dans la première approche (comportementale), l'effet du blocage de ces canaux par la KTX (10 ng) (en injection icv) a été évalué dans différents protocoles mettant en jeu préférentiellement deux types de mémoire dans une tâche de discrimination olfactive : la mémoire procédurale et la mémoire de référence. Dans les deux types de mémoire étudiée, le blocage de ces canaux par la KTX facilitait l'apprentissage et non la consolidation des informations. Cette toxine facilitait également le rappel à long-terme d'une association odeur-renforcement. Une expérience contrôle en open-field a montré que le blocage des canaux KV1.1 et KV1.3 par la KTX n'affectait pas les processus d'attention. La deuxième approche (électrophysiologique) avait pour but d'explorer les éventuels phénomènes de plasticité pouvant sous-tendre la facilitation de l'apprentissage induit par la KTX. Une première expérience, "in vitro" sur tranche d'hippocampe, a montré que la KTX (100 nM) induisait une facilitation synaptique de longue durée vraisemblablement par un mécanisme pré-synaptique au niveau des synapses fibres moussues-CA3. Ce résultat a été ensuite confirmé par une expérience réalisée "in vivo" chez le rat éveillé libre de ses mouvements avec une dose de 10 ng en icv. La troisième approche (histochimique) avait pour but d'observer une éventuelle implication de ces canaux au cours des processus mnésiques. La technique d'hybridation in situ a montré une diminution de l'expression des ARNm KV1.1 au niveau de l'hippocampe ventral (GD, CA3 et CA1) lorsque les rats étaient sacrifiés 1 heure après la seconde séance d'apprentissage d'une association odeur-renforcement. D'autres variations ont été observées, mais ne semblaient pas être spécifiques du conditionnement.AIX-MARSEILLE1-BU Sci.St Charles (130552104) / SudocSudocFranceF

Implication des canaux potassium dépendant du calcium et de faible conductance au cours des processus mnésiques chez le rat (approche comportementale, pharmacologique, biochimique et biomoléculaire)

Cette étude a pour objectif d évaluer l implication des canaux SK (SK1, SK2 et SK3) dans les processus d apprentissage et de mémorisation. Dans un premier temps, nous avons comparé les effets de l apamine, une toxine inactivant les canaux SK composés des sous-unités SK2 et SK3 à ceux de la Lei-Dab7, spécifique, à haute affinité uniquement, de la sous-unité SK2, au cours processus mnésiques. Injectées par voie intracérébroventriculaire, l'apamine induit une facilitation mnésique durant la consolidation des informations alors que la Lei-Dab7 n a aucun effet dans un même contexte de mémorisation. Dans un second temps, nous avons évalué la variation de la densité des canaux SK ainsi que leur expression dans le cerveau de rats à différents stades d'apprentissage. L'apprentissage induit une diminution transitoire de la densité des sites de fixation de l'apamine due à une régulation de l expression des ARNm SK2 et SK3 au niveau de l hippocampe. Ainsi l'inactivation des canaux SK par l'apamine renforcerait l'impact de la "downregulation" transitoire des canaux SK sur l'augmentation de l'excitabilité hippocampique observée lors des processus mnésiques.AIX-MARSEILLE1-BU Sci.St Charles (130552104) / SudocSudocFranceF

Plasticity of the histamine H 3 receptors after acute vestibular lesion in the adult cat

International audienceAfter unilateral vestibular neurectomy (UVN) many molecular and neurochemical mechanisms underlie the neurophysiological reorganizations occurring in the vestibular nuclei (VN) complex, as well as the behavioral recovery process. As a key regulator, the histaminergic system appears to be a likely candidate because drugs interfering with histamine (HA) neurotransmission facilitate behavioral recovery after vestibular lesion. This study aimed at analyzing the post-lesion changes of the histaminergic system by quantifying binding to histamine H 3 receptors (H 3 R; mediating namely histamine autoinhibition) using a histamine H 3 3 receptor agonist ([ H]N-α-methylhistamine). Experiments were done in brain sections of control cats (N = 6) and cats submitted to UVN and killed 1 (N = 6) or 3 (N = 6) weeks after the lesion. UVN induced a bilateral decrease in binding density of the agonist [ 3 H]N-α-methylhistamine to H 3 R in the tuberomammillary nuclei (TMN) at 1 week post-lesion, with a predominant down-regulation in the ipsilateral TMN. The bilateral decrease remained at the 3 weeks survival time and became symmetric. Concerning brainstem structures, binding density in the VN, the prepositus hypoglossi, the subdivisions of the inferior olive decreased unilaterally on the ipsilateral side at 1 week and bilaterally 3 weeks after UVN. Similar changes were observed in the subdivisions of the solitary nucleus only 1 week after the lesion. These findings indicate vestibular lesion induces plasticity of the histamine H 3 R, which could contribute to vestibular function recovery

DIFFERENTIAL EFFECTS OF TWO BLOCKERS OF SMALL CONDUCTANCE Ca 2+ -ACTIVATED K + CHANNELS, APAMIN AND LEI-DAB7, ON LEARNING AND MEMORY IN RATS

International audienceSK channels are responsible for long-lasting hyperpolarization following action potential and contribute to the neuronal integration signal. This study evaluates the involvement of SK channels on learning and memory in rats, by comparing the effects of two SK channel blockers, i.e., apamin which recognizes SK2 and SK3 channels, and lei-Dab7 which binds SK2 channels only. lei-Dab7 totally competes and contests apamin binding on whole brain sections (IC(50): 11.4 nM). Using an olfactory associative task, intracerebroventricular blocker injections were tested on reference memory. Once the task was mastered with one odor pair, it was then tested with a new odor pair. Apamin (0.3 ng), injected before or after the acquisition session, improved new odor pair learning in a retention session 24 hours later, whereas lei-Dab7 (3 ng) did not significantly affect the mnesic processes. These results indicated that the blockage of SK channels by apamin facilitates consolidation on new odor associations; lei-Dab7, containing only SK2 subunits, remains without effect suggesting an involvement of SK3 channels in the modulation of the mnesic processes

Differential effects of two blockers of small conductance Ca(2+)-activated K(+) channels, apamin and lei-DAB7, on learning and memory in rats

International audienceSK channels are responsible for long-lasting hyperpolarization following action potential and contribute to the neuronal integration signal. This study evaluates the involvement of SK channels on learning and memory in rats, by comparing the effects of two SK channel blockers, i.e., apamin which recognizes SK2 and SK3 channels, and lei-Dab7 which binds SK2 channels only. lei-Dab7 totally competes and contests apamin binding on whole brain sections (IC(50): 11.4 nM). Using an olfactory associative task, intracerebroventricular blocker injections were tested on reference memory. Once the task was mastered with one odor pair, it was then tested with a new odor pair. Apamin (0.3 ng), injected before or after the acquisition session, improved new odor pair learning in a retention session 24 hours later, whereas lei-Dab7 (3 ng) did not significantly affect the mnesic processes. These results indicated that the blockage of SK channels by apamin facilitates consolidation on new odor associations; lei-Dab7, containing only SK2 subunits, remains without effect suggesting an involvement of SK3 channels in the modulation of the mnesic processes

Apamin treatment accelerates equilibrium recovery and gaze stabilization in unilateral vestibular neurectomized cats: Cellular and behavioral aspects

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Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats

Voltage-gated potassium channels (Kv) are critically involved in learning and memory processes. It is not known, however, whether the expression of the Kv1.1 subunit, constituting Kv1 channels, can be specifically regulated in brain areas important for learning and memory processing. Radioactive in situ hybridization was used to evaluate the content of Kv1.1 α-subunit mRNA in the olfactory bulb, ventral, and dorsal hippocampus at different stages of an odor-discrimination associative task in rats. Naive, conditioned, and pseudoconditioned animals were sacrificed at different times either prior to a two-odor significance learning or after odor discrimination was established. Important decreases of Kv1.1 mRNA levels were transiently observed in the ventral hippocampus before successful learning when compared with the pseudoconditioned group. Moreover, temporal group analysis showed significant labeling alterations in the hippocampus of conditioned and pseudoconditioned groups throughout the training. Finally, Kv1.1 mRNA levels in the hippocampus were positively correlated with odor-reward association learning in rats that were beginning to discriminate between odors. These findings indicate that the Kv1.1 subunit is transiently down-regulated in the early stages of learning and suggest that Kv1 channel expression regulation is critical for the modification of neuronal substrates underlying new information acquisition

Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson's disease

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