Differential structural plasticity of corticostriatal and thalamostriatal axo‐spinous synapses in MPTP‐treated parkinsonian monkeys

Abstract

Striatal spine loss is a key pathological feature of Parkinson's disease (PD). Knowing that striatal glutamatergic afferents target dendritic spines, these data appear difficult to reconcile with evidence for an increased expression of the vesicular glutamate transporter 1 (vGluT1) in the striatum of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, as well as in some electrophysiological studies showing overactivity of the corticostriatal glutamatergic system in models of parkinsonism. To address the possibility that structural changes in glutamatergic afferents may underlie these discrepancies, we undertook an ultrastructural analysis of vGluT1-positive (i.e., corticostriatal) and vGluT2-positive (i.e., mostly thalamostriatal) axo-spinous glutamatergic synapses using a 3D electron microscopic approach in normal and MPTP-treated monkeys. Three main conclusions can be drawn: 1) spines contacted by vGluT1-containing terminals have larger volume and harbor significantly larger postsynaptic densities (PSDs) than those contacted by vGluT2-immunoreactive boutons; 2) a subset of vGluT2-, but not vGluT1-immunoreactive, terminals display a pattern of multisynaptic connectivity in normal and MPTP-treated monkeys; and 3) VGluT1- and vGluT2-positive axo-spinous synapses undergo ultrastructural changes (larger spine volume, larger PSDs, increased PSD perforations, larger presynaptic terminal) indicative of increased synaptic activity in parkinsonian animals. Furthermore, spines contacted by cortical terminals display an increased volume of their spine apparatus in MPTP-treated monkeys, suggesting an increased protein synthesis at corticostriatal synapses. These findings demonstrate that corticostriatal and thalamostriatal glutamatergic axo-spinous synapses display significantly different ultrastructural features, and that both systems undergo complex morphological changes that could underlie the pathophysiology of corticostriatal and thalamostriatal systems in PD.

Relationship between oscillatory activity in the cortico-basal ganglia network and parkinsonism in MPTP-treated monkeys

“…This suggests that the observed coherence changes are associated with, but are not causal of, parkinsonism, and that they may not be primarily dopaminergic in origin. It is possible that these coherence changes result instead from other changes in the basal ganglia, thalamus, or cortex that are known to accompany parkinsonism in human PD and in MPTP-treated primates, such as changes in striatal spine density, loss of the thalamostriatal system, or changes in non-dopaminergic transmitter systems, such as the noradrenergic or serotonergic systems (Villalba and Smith, 2011; Villalba et al, 2009). Such changes would not be expected to be reversible by acute stimulation of dopamine receptors.…”

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

“…These findings also provide a proof-of-principle demonstration that in patients suffering from decreased PSD-95 levels, as occurs in ASD, restoration Electron microscopic analysis. As described previously (65), PSD measurements were performed with ImageJ software (NIH) by an observer blinded to the genotype of the animals. Results are expressed as the mean ± SEM.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…These include a growing list of chronic morphological changes in the basal ganglia, affecting glutamatergic and GABAergic transmission in these structures. For instance, plasticity at glutamatergic synapses has been demonstrated in animal models of parkinsonism and in patients with PD, affecting the corticostriatal, thalamostriatal, and corticosubthalamic pathways [166][167][168][169][170][171][172][173]. Recent studies have suggested additional plasticity of the GABAergic collaterals within the GPe, as well as the pallidosubthalamic projection, the latter perhaps related to heterosynaptic homeostatic modulations, driven by N-methyl-D-aspartate receptor activation at corticosubthalamic synapses [157,158,174].…”