RESUMO
Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca2+ signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.
Assuntos
Corpo Estriado/metabolismo , Plasticidade Neuronal/genética , Receptores 5-HT4 de Serotonina/genética , Serotonina/metabolismo , Tálamo/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Indóis/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Depressão Sináptica de Longo Prazo , Camundongos , Camundongos Transgênicos , Vias Neurais , Plasticidade Neuronal/efeitos dos fármacos , Optogenética , Piperidinas/farmacologia , Propano/análogos & derivados , Propano/farmacologia , Antagonistas do Receptor 5-HT4 de Serotonina/farmacologia , Sulfonamidas/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Tálamo/citologia , Tálamo/efeitos dos fármacosRESUMO
Activation of GABA(A) receptors by GABA causes phasic and tonic conductances in different brain areas. In the ventrobasal (VB) thalamus, tonic inhibition originates from GABA acting on extrasynaptic receptors. Here we show that dopamine (DA), the D2-like agonist quinpirole and the selective D4R agonist PD-168,077 decrease the magnitude of the tonic GABA(A) current while D1-like agonist SKF39383 lacks any significant effects in VB neurons of Wistar rats. On the other hand, DA and D1/D2 receptor activation does not alter phasic GABA(A) conductance. As we previously reported that an increased tonic GABA(A) current in VB neurons is critical for absence seizure generation, we also investigated whether D2-D4 receptor activation is capable of normalizing this aberrant conductance in genetic absence epilepsy rats from Strasbourg (GAERS). Quinpirole and PD-168,077 selectively reduces tonic GABA(A) current as in normal rats. Therefore, it is conceivable that some DA anti-absence effects occur via modulation of tonic GABA(A) current in the VB.