Striatal plasticity and medium spiny neuron dendritic remodeling in parkinsonism

Abstract

Current approaches to Parkinson's Disease (PD) are largely based on our current understanding of the mechanisms that contribute to the death of nigrostriatal dopamine neurons. However, our understanding of the consequences of the loss of dopamine on the striatal target cells of nigrostriatal neurons is much less advanced. In particular, the compensatory changes that occur in striatal medium spiny neurons (MSNs) that have lost their normal dopamine input remains poorly understood. The compensatory changes may have either positive or negative effects. Among the alterations that occur in striatal cells of the dopamine-denervated striatum are dystrophic changes in the dendrites of MSNs, with a loss of dendritic length and dendritic spine number. Dendritic spines are the targets of convergent nigrostriatal dopamine and corticostriatal glutamate axons, and integrate these convergent signals to determine the nature of striatal output. The loss of these spines in the dopamine-denervated state may protect the MSN from overt excitotoxic death, but at the price of compromising MSN function. The loss of dendritic spines is thought be responsible for the gradual decrease in levodopa efficacy in late-stage PD, suggesting that therapeutic interventions need to be developed that target key downstream signaling complexes in medium spiny neurons.

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

“…MSN spine loss is present starting about 2 weeks after striatal dopamine depletion and persisting for at least 12 months (Ingham et al 1989;Deutch et al 2007). Animals survived for 4 weeks after the cortical lesions before being sacrificed.…”

“…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. Dopamine replacement treatment in PD patients or in animals with striatal dopamine depletion does not restore spine loss (Stephens et al 2005;Zaja-Milatovic et al 2005;Deutch et al 2007), suggesting that the dopamine receptor is uncoupled from its intracellular effectors.…”

“…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. Dopamine replacement treatment in PD patients or in animals with striatal dopamine depletion does not restore spine loss (Stephens et al 2005;Zaja-Milatovic et al 2005;Deutch et al 2007), suggesting that the dopamine receptor is uncoupled from its intracellular effectors. This led us to hypothesize that manipulating corticostriatal glutamate release directly might reverse the MSN spine loss seen in the dopamine-denervated striatum.…”

Comparision of Dynamic Behaviors of Striatal Population With Two Different Neuron Models: Hodgkin-Huxley and Izhikevich

“…Depending on the species, MSNs comprise 90-95% of the total neuronal population in the striatum of the basal ganglia and they suppress the other structures which are affected by the striatum. On the other hand, interneurons comprise only ~10% of the striatal cells [1,2].Considering these ratios, as in a striatal microcircuit, in all architectures one interneuron is considered along with 20 medium spinny (MS) neurons.…”

“…Striatum which receives input from the cerebral cortex is also the primary input to the basal ganglia system. 90-95% of the total neuronal population of the striatum comprise medium spiny neurons (MSN) which have dopamine receptors [1,2]. The lack of dopamine in the striatum is regarded as a major cause of motor-related Parkinson's disease symptoms, such as tremors, bradykinesia, and postural instability.…”