Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Abstract

Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.

Keywords: experimental autoimmune encephalomyelitis; hippocampus; interleukin-1β; long-term potentiation; multiple sclerosis; synaptic plasticity.

Figure 1.

TBS-induced plasticity in MS and healthy controls. (a) iTBS induces the expected effects in MS Gd⁻ (grey line) patients and in healthy subjects (HS, dotted line) but is altered in MS Gd⁺ (black line) patients. Gd⁻ patients and the control group display the predictable LTP-like effect, while in MS Gd⁺ patients no plastic changes of cortical excitability are observed (adapted from [21]). (b) cTBS-induced effects diverge between MS (solid line) patients and healthy control subjects (HS, dotted line). The control group displays the predictable LTD-like effect, while MS patients manifest LTP-like changes. *p < 0.05, ANOVA.

Figure 2.

Shifted hippocampal frequency–response function in EAE mice and in response to IL-1β. (a) Superimposed pooled data showing the normalized changes in field potential slope (±s.e.m.) (CFA, n = 11; EAE, n = 12) induced by paired-pulse low-frequency stimulation protocol (PP-LFS: 1 Hz, 15 min). Here and after, insets show field EPSPs from representative experiments during a baseline interval and 60 min after delivery of conditioning train. (b) Superimposed pooled data showing the normalized changes in field potential slope (±s.e.m.) (CFA, n = 9; EAE, n = 12) induced by high-frequency stimulation (HFS: 100 Hz; 1 s). (c) Frequency–response function in EAE and CFA mice. The graph shows the percentage change in synaptic strength from baseline in EAE and CFA animals at 60 min in response to a variety of conditioning trains (at least seven slices were tested for each condition). Values are mean (±s.e.m.). *p < 0.05 (t-test) at all frequencies tested. (d) Superimposed pooled data showing the normalized changes in field potential slope (±s.e.m.) induced by PP-LFS in CFA animals with (n = 10) or without (n = 11) IL-1β application (30 ng ml⁻¹, duration of application indicated by bar). (e) Superimposed pooled data showing the normalized changes in field potential slope (±s.e.m.) induced by HFS in CFA animals with (n = 9) or without (n = 9) IL-1β application. (f) Shown is a frequency–response graph of the fEPSP changes in response to a variety of conditioning trains in CFA animals with or without IL-1β (at least seven slices were tested for each condition). Values are mean (±s.e.m.). *p < 0.05 (t-test) at all frequency tested (adapted from [17]). (a­–c) Black circles, CFA; white circles, EAE and (d–f) grey circles, CFA+IL-1β; black circles, CFA+vehicle.

Figure 3.

Loss of PV+ interneurons in the EAE hippocampus. (a–d) Immunostaining of Iba1+ microglia cells (upper panels), DAPI cell nuclei (grey, upper panels) and PV+ neurons (lower panels), in hippocampal coronal sections derived from CFA (a) and EAE mice at 20 d.p.i. (b), respectively. A strong microglia activation and loss of PV+ neurons characterize EAE hippocampus. (c) and (d) are high magnifications of the white boxes in (a) and (b), respectively. The number of PV+ interneurons (lower panels) in the CA1 layer and stratum oriens was reduced in EAE mice relative to CFA mice. (e) Histogram shows the mean percentage of the PV+ density interneurons (1 mm⁻²) which was significantly reduced in EAE mice by about 27% relative to CFA in the acute phase of the disease. **p < 0.01, t-test. Scale bars: (a,b) 200 μm, (c,d) 100 μm. (Online version in colour.)