Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible

Abstract

The classical motor symptoms of Parkinson’s disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days. In order to assess the consequences of dopamine depletion, mice were analyzed 21 days after the last injection. In order to test reversibility of MSN changes we exploited the property of this model that striatal axon terminals regenerate by sprouting within 90 days and analyzed a second cohort 90 days after MPTP. Degeneration of dopaminergic neurons was confirmed by counting TH-positive neurons in the substantia nigra and by analyzing striatal catecholamines. Striatal catecholamine recovered 90 days after MPTP. MSN morphology was visualized by Golgi staining and quantified as total dendritic length, number of dendritic branch points, and density of dendritic spines. All morphological parameters of striatal MSN were reduced 21 days after MPTP. Statistical analysis indicated that dendritic pruning and the reduction of spine density represent two distinct responses to dopamine depletion. Ninety days after MPTP, all morphological changes recovered. Our findings demonstrate that morphological changes in striatal MSN resulting from dopamine depletion are reversible. They suggest that under optimal conditions, symptomatic dopaminergic therapy might be able to prevent maladaptive plasticity and long-term motor complications in PD patients.

Role of Stress-Related Dopamine Transmission in Building and Maintaining a Protective Cognitive Reserve

“…DA is required for glutamate-induced spinogenesis and exerts dichotomous effects on neurons expressing the D1 or D2 receptor subtypes so that they store memories of reward and reward omission, respectively, through cell-type-specific spine enlargement [ 90 , 91 ]. Finally, reduced DA availability due to degeneration of DA cells interferes with spinogenesis while increasing pruning [ 92 ].…”

Treating Traumatic Brain Injuries with Electroceuticals: Implications for the Neuroanatomy of Consciousness

“…Interestingly, cerebral glucose metabolism can be used to differentiate MCS− and MCS+ patients, with MCS+ patients showing higher metabolism in left cortical areas crucial for language as well as in the posterior parietal, sensorimotor, premotor, and pre-supplementary motor cortices [30], some of which have direct cortico-thalamic projections from the central thalamus [16]. Projections from the central thalamus also innervate the striatum (caudate, putamen, and nucleus accumbens) and project onto medium spiny neurons [86], which are sensitive to dopamine deficiency [87], and may contribute to positive results seen with amantadine [47][48][49]75] and apomorphine [52,53]. Medium spiny neurons normally function to dis-inhibit the central thalamus by inhibiting the globus pallidus internus.…”

“…NeuroSci 2021, 2, FOR PEER REVIEW of which have direct cortico-thalamic projections from the central thalamus [16]. Pr tions from the central thalamus also innervate the striatum (caudate, putamen, and cleus accumbens) and project onto medium spiny neurons [86], which are sensitive t pamine deficiency [87], and may contribute to positive results seen with amantadine 49,75] and apomorphine [52,53]. Medium spiny neurons normally function to dis-in the central thalamus by inhibiting the globus pallidus internus.…”

Adaptive changes in striatal projection neurons explain the long duration response and the emergence of dyskinesias in patients with Parkinson’s disease

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