Dopaminergic denervation and spine loss in the striatum of MPTP-treated monkeys

Abstract

Striatal spine loss is a key pathological feature of human Parkinson’s disease (PD) that can be induced after complete degeneration of the nigrostriatal dopaminergic system in rodent models of parkinsonism. In line with these observations, our findings reveal a significant (30–50%) reduction in spine density in both the caudate nucleus and putamen of severely DA-depleted striata of MPTP-treated monkeys; the sensorimotor post-commissural putamen being the most severely affected region for both dopamine depletion and spine loss. Using MPTP-treated monkeys with complete or partial striatal dopamine (DA) denervation, we also demonstrate that striatal spine loss is an early pathological feature of parkinsonism, which progresses along a positive rostrocaudal and mediolateral gradient in parallel with the extent of striatal dopamine denervation. Quantitative electron microscopy immunocytochemistry for D1 dopamine receptor (D1) in the striatum of control and severely DA-depleted animals revealed that both D1-immunoreactive and immunonegative spines are lost in the putamen of MPTP-treated monkeys. These data demonstrate that striatal spine loss in MPTP-treated monkeys is an early pathological event of parkinsonism, tightly correlated with the degree of nigrostriatal dopamine denervation that likely affects both direct and indirect striatofugal pathways.

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

“…Thus, we hypothesize here a close relationship between the ethanol withdrawal-induced reduction of DAergic activity and the loss of dendritic spines in the Nacc shell. Such a conclusion would also be consistent with results obtained using 6-hydroxydopamine lesions (30) and the consequent marked decrease in MSN spine density (31)(32)(33). It is also supported by previous data showing that morphine-withdrawn (34) and cannabis-dependent subjects (35) display a loss of dendritic spines paralleled by a reduced DAergic firing (36,37) and impaired DA release (38)(39)(40).…”

Cortical Regulation of Striatal Medium Spiny Neuron Dendritic Remodeling in Parkinsonism: Modulation of Glutamate Release Reverses Dopamine Depletion–Induced Dendritic Spine Loss

“…Several studies have pointed to D 1 -expressing (direct pathway) MSNs as being critical to the development and maintenance of dyskinesias (Bordet et al 2000;Carta et al 2008;Berthet et al 2009;Darmopil et al 2009). In contrast, rodent studies indicate that MSN dendritic spine loss in the dopamine-depleted striatum occurs in D 2 -expressing MSNs (Rodriguez and Pickel 1999;Day et al 2006;Deutch et al 2007), although a recent study in the primate suggests that spines are also lost on D 1 -expressing cells (Villalba et al 2009). Because Golgi impregnation of neurons precludes the determination of the type of MSN, we cannot ascertain if the changes we observed occur in indirect-or direct-pathway MSNs.…”

“…Among these disorders is PD, in which striatal dopamine depletion elicits dystrophic changes of MSN dendrites. Both postmortem studies of PD as well as studies in animal models of parkinsonism have reported a marked decrease in MSN spine density (McNeill et al 1988;Ingham et al 1989Ingham et al , 1993Ingham et al , 1998Arbuthnott et al 2000;Stephens et al 2005;Zaja-Milatovic et al 2005;Day et al 2006;Villalba et al 2009). While the primary cause of this dendritic remodeling is loss of dopamine signaling through the D 2 receptor (Day et al 2006;Deutch et al 2007), it appears likely that changes in cortically derived glutamate contribute to the changes in MSN spines.…”

Serotonin dysregulation in Fragile X Syndrome: implications for treatment

“…Irregularities in dopamine production and/or dopamine receptors are linked to disorders such as autism, schizophrenia, depression, ADHD, and substance abuse. Abnormally high or low levels of dopamine negatively impact dendritic morphology (22,68,69). In a thorough review of the impact of dopamine on brain disorders and neurodevelopment, Money and Stanwood (68) state that examination of all the evidence points to dopamine playing "a crucial role…in formation and stabilization of synaptic connections in the striatum and frontal cortex".…”