Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease

Abstract

Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti-inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre-and post-synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology. More than 50% of MS patients experience cognitive deficits, 1,2 and hippocampal-dependent learning and memory is often impaired.3,4 Hippocampal atrophy has been shown in MS patients using in vivo MRI, 5,6 and this atrophy was correlated with impaired performance on visuospatial memory testing, a hippocampal-dependent function.7 Data from postmortem studies in MS have demonstrated that hippocampal demyelination and neuropathology occur. 8,9 This demyelination has been associated with changes in molecules modulating synaptic integrity, axonal transport and glutamate homeostasis.10 Although evidence from both in vivo MRI and post-mortem pathological studies indicates that hippocampal pathology occurs during MS, the relationship between such pathology and dysfunction remains unclear. Moreover, there are currently no treatments available to prevent hippocampal dysfunction during MS.Demyelination, axonal los...

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

“…Therefore, we hypothesize that the relatively modest effect on localized GM sparing using VBM may be due to a lack of direct neuroprotective effects of natalizumab. Estrogens, in contrast, have been shown to be neuroprotective in a variety of neurologic disease models (Bode et al., 2008; Engler‐Chiurazzi, Brown, Povroznik, & Simpkins, 2017; Spence & Voskuhl, 2012; Suzuki, Brown, & Wise, 2009), including estriol treatment on cognitive electrophysiologic and neuropathologic outcomes in the MS model (Ziehn, Avedisian, Dervin, O'Dell, & Voskuhl, 2012). …”

“…While the protective effect of estriol treatment on MS appears to be mediated in part by anti‐inflammatory mechanisms (Gold et al., 2009; Soldan, Alvarez Retuerto, Sicotte, & Voskuhl, 2003; Voskuhl & Gold, 2012), this is not mutually exclusive of direct neuroprotective effects, as these have been shown in the MS model (Crawford et al., 2010; Kim et al., 2018; MacKenzie‐Graham et al., 2012; Spence et al., 2011). Together, preclinical data in EAE have shown that estriol is acting to decrease microglial activation, induce remyelination, and increase synaptic plasticity (Kim et al., 2018; Ziehn et al., 2012). Further, we have shown that treatment with estrogens and estrogen receptor ligands prevented both cortical and cerebellar GM atrophy by MRI, which correlated with preserving axons, neurons, and synapses in EAE (Itoh et al., 2017; Kim et al., 2018; MacKenzie‐Graham et al., 2012).…”

XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis

“…Much of the literature on the origins of sex-biased neurological diseases has focused on the role of sex steroid hormones, particularly the role of estrogen and testosterone in neuroprotection (20,21,(25)(26)(27)(28). The increased female bias for MS could theoretically result from deleterious effects of physiologic levels of female sex hormones or protective effects of male sex hormones.…”

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

“…34,35 In addition, oestrogen treatment improves cognitive dysfunction in women without multiple sclerosis who have had ovariectomy, 36 and oestrogen treatment of ovariectomised animals increases dendritic spines and synapses in cerebral grey matter. [37][38][39] We showed that higher serum estriol concentrations might be needed for benefi cial eff ects on cognition. Cortical grey matter sparing in the estriol group compared with the placebo group was lost at 24 months, when both estriol concentrations and PASAT scores had decreased.…”