RESUMO
Striatal projection neurons (SPNs) process motor and cognitive information. Their activity is affected by Parkinson's disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.
Assuntos
Potenciais de Ação , Neurônios GABAérgicos/fisiologia , Canais de Potássio KCNQ/fisiologia , Neostriado/fisiologia , Sinapses/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Córtex Cerebral/fisiologia , Neurônios Colinérgicos/fisiologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Transgênicos , Muscarina/farmacologia , Agonistas Muscarínicos/farmacologia , Neostriado/citologia , Neostriado/metabolismo , Peptídeos/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMO
Growing evidence indicates that the activity of infralimbic prefrontal cortex (IL) is critical for inhibiting inappropriate fear responses following extinction learning. Recently, we showed that fear conditioning and extinction alter the intrinsic excitability and bursting of IL pyramidal neurons in brain slices. IL neurons from Sprague Dawley rats expressing high fear had lower intrinsic excitability and bursting than those from rats expressing low fear, suggesting that regulating the intrinsic excitability and bursting of IL neurons would modulate fear expression. To test this, we combined patch-clamp electrophysiology, auditory fear conditioning, and IL infusions of M-type K(+) channel modulators. Patch-clamp recordings from IL neurons showed that the M-type K(+) channel blocker, XE-991, increased the number of spikes evoked by a depolarizing pulse and reduced the first interspike interval indicating enhanced bursting. To test whether pharmacological enhancement of IL excitability and bursting reduces fear expression and facilitates extinction, fear-conditioned rats were infused with XE-991 into IL before extinction training. XE-infused rats showed reduced freezing and facilitated extinction compared to vehicle-infused rats. The following day, recall of extinction memory was enhanced. Reducing IL excitability and bursting with the M-type K(+) channel agonist, flupirtine, had the opposite effect. Flupirtine reduced IL spike count and bursting in brain slices. Fear-conditioned rats infused with flupirtine into IL before extinction showed significantly higher levels of freezing, indicating that stimulation of M-channels enhanced fear expression. Our findings suggest that the intrinsic excitability and bursting of IL neurons regulate fear expression even before extinction.