Abstract
The striatum contains several types of neurons including medium spiny projection neurons (MSNs), cholinergic interneurons (ChIs), and fast-spiking interneurons (FSIs). Modulating the activity of these neurons by the dopamine D2 receptor (D2R) can greatly impact motor control and movement disorders. D2R exists in two isoforms: D2L and D2S. Here, we assessed whether alterations in the D2L and D2S expression levels affect neuronal excitability and synaptic function in striatal neurons. We observed that quinpirole inhibited the firing rate of all three types of striatal neurons in wild-type (WT) mice. However, in D2L knockout (KO) mice, quinpirole enhanced the excitability of ChIs, lost influence on spike firing of MSNs, and remained inhibitory effect on spike firing of FSIs. Additionally, we showed mIPSC frequency (but not mIPSC amplitude) was reduced in ChIs from D2L KO mice compared with WT mice, suggesting spontaneous GABA release is reduced at GABAergic terminals onto ChIs in D2L KO mice. Furthermore, we found D2L deficiency resulted in reduced dendritic spine density in ChIs, suggesting D2L activation plays a role in the formation/maintenance of dendritic spines of ChIs. These findings suggest new molecular and cellular mechanisms for causing ChIs abnormality seen in Parkinson’s disease or drug-induced dyskinesias.
Highlights
The striatum, a main input nucleus of the basal ganglia, plays an important role in motor control, reward processing, and habit formation [1,2] and is involved in the pathophysiology of movement disorders, such as Parkinson’s disease (PD) and dyskinesias [3,4].The physiological properties and function of neurons in the striatum are heterogeneous.Medium-sized spiny neurons (MSNs) constitute approximately 95% of the total neuronal population in rodent striatum [5]
MSNs are GABAergic projection neurons. They send efferents to other basal ganglia nuclei through two main pathways: a direct pathway mediated by the dopamine D1 receptor (D1R), and an indirect pathway mediated by the dopamine D2 receptor (D2R) [6,7]
To assess if the deletion of D2L would alter the excitability of striatal neurons, we examined the effect of quinpirole, a preferential D2R agonist, on three types of striatal neurons: MSNs, cholinergic interneurons (ChIs), and fast-spiking interneurons (FSIs)
Summary
The striatum, a main input nucleus of the basal ganglia, plays an important role in motor control, reward processing, and habit formation [1,2] and is involved in the pathophysiology of movement disorders, such as Parkinson’s disease (PD) and dyskinesias [3,4].The physiological properties and function of neurons in the striatum are heterogeneous.Medium-sized spiny neurons (MSNs) constitute approximately 95% of the total neuronal population in rodent striatum [5]. The striatum, a main input nucleus of the basal ganglia, plays an important role in motor control, reward processing, and habit formation [1,2] and is involved in the pathophysiology of movement disorders, such as Parkinson’s disease (PD) and dyskinesias [3,4]. The physiological properties and function of neurons in the striatum are heterogeneous. They send efferents to other basal ganglia nuclei through two main pathways: a direct pathway mediated by the dopamine D1 receptor (D1R), and an indirect pathway mediated by the dopamine D2 receptor (D2R) [6,7]. The direct pathway sends projections from the striatum directly to the substantia nigra pars reticulata (SNr). An adequate balance between these two output pathways is crucial for motor control and various cognitive functions
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