RESUMO
Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.
Assuntos
Globo Pálido/fisiologia , Neurônios Motores/fisiologia , Inibição Neural/fisiologia , Tálamo/fisiologia , Potenciais de Ação/fisiologia , Oxirredutases do Álcool/genética , Animais , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/fisiologia , Dopamina/metabolismo , Distonia/dietoterapia , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Feminino , Globo Pálido/citologia , Globo Pálido/metabolismo , Levodopa/uso terapêutico , Masculino , Erros Inatos do Metabolismo/dietoterapia , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/fisiopatologia , Camundongos , Camundongos Knockout , Contração Muscular/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Transtornos Psicomotores/dietoterapia , Transtornos Psicomotores/tratamento farmacológico , Transtornos Psicomotores/fisiopatologia , Tálamo/citologiaRESUMO
Tetrahydrobiopterin (BH(4)) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH(4) is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH(4) deficiency has been shown to be closely associated with diverse neurological psychiatric disorders. Sepiapterin reductase (SPR) is an enzyme that catalyzes the final step of BH(4) biosynthesis. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in BH(4) biosynthesis and metabolism has been increasing, only a handful of cases of SPR deficiency have been reported, and the role of SPR in BH(4) biosynthesis in vivo has been poorly understood. Here, we report that mice deficient in the Spr gene (Spr(-/-)) display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH(4) and for the normal functions of BH(4)-dependent enzymes. The Spr(-/-) mice exhibit phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH(4) and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr(-/-) mice share striking similarities with the symptoms observed in SPR-deficient patients. This Spr mutant strain of mice will be an invaluable resource to elucidate many important issues regarding SPR and BH(4) deficiencies.