Minocycline differentially modulates human spatial memory systems

Abstract

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer's pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary-and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary-compared to landmark-based information (t 980 = 3.140, p = 0.002). However, though this marginally improved performance for boundary-based objects (t 980 = 1.972, p = 0.049), it was outweighed by impaired landmark-based navigation (t 980 = 6.374, p < 0.001) resulting in an overall performance decrease (t 980 = 3.295, p = 0.001). Furthermore, against expectations, minocycline significantly reduced activity during memory encoding in the right caudate (t 977 = 2.992, p = 0.003) and five other cortical regions, with no significant effect in the hippocampus. In summary, minocycline impaired human spatial memory performance, likely through disruption of striatal processing resulting in greater biasing towards reliance on boundary-based navigation.

Acute minocycline treatment inhibits microglia activation, reduces infarct volume, and has domain-specific effects on post-stroke cognition in rats

“…In the present study, we used a MWM task to assess hippocampal-based spatial learning and reference memory and found minocycline-treated rats presented with a mild de cit in spatial learning but not reference memory. Whereas rodent models of stroke and aging have previously reported improvements in hippocampal function with minocycline treatment [39][40][41] , our results align more closely with a clinical study that found minocycline impaired spatial memory performance 42 . Pathologically, we assessed microglia and astrocyte expression in the hippocampus but found no treatment differences, suggesting that other mechanisms are likely involved.…”

“…To date, experimental stroke studies utilizing minocycline have employed behavioural tasks to assess hippocampal and motor function but have lacked testing in executive domains. Rodent models have observed improvements in hippocampal function with minocycline treatment [39][40][41] but, a study in healthy humans found that minocycline could impair spatial memory 42 , emphasizing variability across species and the need for further cognitive testing. Overall, the possible differential effects of post-stroke minocycline treatment across cognitive domains are unknown.…”

The role of sleep disturbance and inflammation for spatial memory

“…In another placebo-controlled study ( Reichenberg et al., 2001 ), healthy subjects received an intravenous injection of LPS, which caused a disruption of figural memory (a memory form functionally related to spatial memory), and these LPS-induced memory impairments correlated with systemic concentrations of TNF-α. However, in contrast to these findings, a recent placebo-controlled study found that treatment with minocycline, a centrally penetrant antibiotic with anti-inflammatory properties, in fact, resulted in an impairment of spatial memory performance ( Berens et al., 2020 ).…”

Attenuating human fear memory retention with minocycline: a randomized placebo-controlled trial

“…In aged animals and in Alzheimer’s disease models [ 27 – 29 ], prolonged minocycline treatment has been shown to improve hippocampus-dependent spatial memory. However, this improvement is not observed in non-aged healthy animals or humans [ 30 ]. In the latter study, in fact, prolonged minocycline treatment markedly reduced landmark-based spatial memory [ 30 ], in line with its potential effect on synaptic consolidation.…”