Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis

Abstract

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.

Figures

Figure 1.

Cortical excitability changes induced by (A) iTBS and (B) cTBS in RR-MS, PP-MS, and HSs. *p < 0.05.

Figure 2.

PDGF levels in the CSF of MS subjects. The graph shows that PDGF was significantly lower in PP-MS patients than in RR-MS. *p < 0.05, versus RR-MS.

Figure 3.

Effect of PDGF on hippocampal synaptic function. A, Input/output curves are shown as plots of the fEPSP slopes against the corresponding presynaptic fiber volley amplitudes. Each treatment group is the average (±SEM) of at least six recordings performed on separate slices. No significant differences between treatment groups were detected. B, Time plot of fEPSP responses showing that pretreatment with PDGF enhances the magnitude of CA1-LTP. Representative fEPSP recordings from time points 1 and 2 are shown for each condition. Calibration: 0.5 mV, 10 ms.

Figure 4.

Association between PDGF levels and clinical compensation in RR-MS. A, The histogram shows that PDGF CSF levels were lower in Gd+ relapsing patients than in Gd+ clinically silent patients. B, Relapsing patients were more frequent among RR-MS subjects with undetectable PDGF levels at the time of MRI activation. *p < 0.05.

Figure 5.

PDGF favors LTP over LTD in RR-MS patients. Correlation plot shows that PDGF levels in the CSF correlate with the magnitude of LTP-like changes induced 15 min after cTBS in RR-MS patients.