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1.
Proc Natl Acad Sci U S A ; 101(25): 9474-8, 2004 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-15194823

RESUMO

Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca(2+)-activated K(+) channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK(-/-)) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK(-/-) mice showed a dramatic reduction in spontaneous activity of the BK(-/-) cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia.


Assuntos
Ataxia Cerebelar/fisiopatologia , Canais de Potássio Cálcio-Ativados/fisiologia , Células de Purkinje/fisiologia , Animais , Piscadela/fisiologia , Feminino , Hibridização In Situ , Canais de Potássio Ativados por Cálcio de Condutância Alta , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Knockout , Canais de Potássio Cálcio-Ativados/deficiência , Canais de Potássio Cálcio-Ativados/genética , Sinapses/fisiologia
2.
J Neurophysiol ; 91(2): 1102-7, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14534284

RESUMO

In heterozygous Lurcher mice (Lc/+), the Purkinje cells (PCs) degenerate almost totally during postnatal development. On the other hand, their projection target, the deep cerebellar nuclei (DCN), shows few signs of degeneration and seems to play an important role in maintaining a residual cerebellar function in Lc/+. We asked whether the DCN in Lc/+ develop cellular adaptations allowing them to cope with the loss of GABAergic PC input. Using whole-cell patch-clamp recordings, we measured inhibitory postsynaptic currents from DCN of Lc/+ and wild-type mice (WT). In experiments on phenotypically striking Lc/+ studied well after the onset of the PC degeneration, we found enlarged average synaptic conductances (g(syn)) compared with WT. We next investigated postnatal mice before and after the onset of PC death. In younger animals

Assuntos
Senescência Celular/fisiologia , Núcleos Cerebelares/fisiologia , Condução Nervosa/fisiologia , Células de Purkinje/citologia , Células de Purkinje/fisiologia , Receptores de GABA-A/fisiologia , Transmissão Sináptica/fisiologia , Animais , Animais Recém-Nascidos , Morte Celular/fisiologia , Núcleos Cerebelares/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Mutantes Neurológicos
3.
J Neurophysiol ; 82(3): 1465-76, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10482762

RESUMO

In the present report, we provide evidence that mesencephalic trigeminal (Mes-V) sensory neurons, a peculiar type of primary afferent cell with its cell body located within the CNS, may operate in different functional modes depending on the degree of their membrane polarization. Using intracellular recording techniques in the slice preparation of the adult rat brain stem, we demonstrate that when these neurons are depolarized, they exhibit sustained, high-frequency, amplitude-modulated membrane potential oscillations. Under these conditions, the cells discharge high-frequency trains of spikes. Oscillations occur at membrane potential levels more depolarized than -53 +/- 2.3 mV (mean +/- SD). The amplitude of these oscillations increases with increasing levels of membrane depolarization. The peak-to-peak amplitude of these waves is approximately 3 mV when the cells are depolarized to levels near threshold for repetitive firing. The frequency of oscillations is similar in different neurons (108.9 +/- 15.5 Hz) and was not modified, in any individual neuron, by changes in the membrane potential level. These oscillations are abolished by hyperpolarization and by TTX, whereas blockers of voltage-dependent K+ currents slow the frequency of oscillations but do not abolish the activity. These data indicate that the oscillations are generated by the activation of inward Na+ current/s and shaped by voltage-dependent K+ outward currents. The oscillatory activity is not modified by perfusion with low-calcium, high-magnesium, or cobalt-containing solutions nor is it modified in the presence of cadmium or Apamin. These results indicate that a calcium-dependent K+ current does not play a significant role in this activity. We postulate that the membrane oscillatory activity in Mes-V neurons is synchronized in adjoining electrotonically coupled cells and that this activity may be modulated in the behaving animal by synaptic influences.


Assuntos
Mesencéfalo/fisiologia , Neurônios Aferentes/fisiologia , Potenciais de Ação/fisiologia , Animais , Cálcio/fisiologia , Potenciais da Membrana/fisiologia , Mesencéfalo/citologia , Neurônios Aferentes/metabolismo , Oscilometria , Bloqueadores dos Canais de Potássio , Ratos , Ratos Wistar , Tetrodotoxina/farmacologia
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