RESUMEN
The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients.
Asunto(s)
Ganglios Basales/metabolismo , Dopamina/metabolismo , Sistema Límbico/metabolismo , Corteza Motora/metabolismo , Neuronas/metabolismo , Porción Reticular de la Sustancia Negra/metabolismo , Receptor Cannabinoide CB1/metabolismo , Potenciales de Acción/fisiología , Animales , Ganglios Basales/efectos de los fármacos , Modelos Animales de Enfermedad , Electrodos , Inmunohistoquímica , Sistema Límbico/efectos de los fármacos , Masculino , Corteza Motora/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson/metabolismo , Porción Reticular de la Sustancia Negra/citología , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Receptor Cannabinoide CB1/fisiología , Simpatectomía Química , Simpaticolíticos/toxicidadRESUMEN
The endocannabinoid system modulates synaptic plasticity in the hippocampus, but a link between long-term synaptic plasticity and the type 1 cannabinoid (CB1) receptor at medial perforant path (MPP) synapses remains elusive. Here, immuno-electron microscopy in adult mice showed that â¼26% of the excitatory synaptic terminals in the middle 1/3 of the dentate molecular layer (DML) contained CB1 receptors, and field excitatory postsynaptic potentials evoked by MPP stimulation were inhibited by CB1 receptor activation. In addition, MPP stimulation at 10â¯Hz for 10â¯min triggered CB1 receptor-dependent excitatory long-term depression (eCB-eLTD) at MPP synapses of wild-type mice but not on CB1-knockout mice. This eCB-eLTD was group I mGluR-dependent, required intracellular calcium influx and 2-arachydonoyl-glycerol (2-AG) synthesis but did not depend on N-methyl-d-aspartate (NMDA) receptors. Overall, these results point to a functional role for CB1 receptors with eCB-eLTD at DML MPP synapses and further involve these receptors in memory processing within the adult brain.