DEFICIENT MEMORY, LONG-TERM POTENTIATION AND HIPPOCAMPAL SYNAPTIC PLASTICITY IN GALECTIN-4-KO MICE

Intestinal infections trigger inflammation and may contribute to degenerative and cognitive brain pathologies through the microbiota-gut-brain axis. Galectin-4 is a key intestinal lectin in the control of pathogenic bacterial infections. In this work, we show that galectin-4-deficient mice (Lgals4-KO) present an altered commensal intestinal microbiota compared to wild-type (WT) animals. This defines a new role for galectin-4 in the modulation of commensal bacteria. Surprisingly, considering that galectin-4 presents only a residual expression in the nervous system of WT mice, Lgals4-KO mice present a neurological deficiency at the level of memory formation according to specific behavioral assays, as well as an impaired long-term potentiation (LTP) in the hippocampus measured by electrophysiological means, both in vivo and ex vivo (hippocampal slices in organotypic culture). Furthermore, Lgals4-KO neuron cultures upon chemical induction of LTP show reduced activation of the AMPA receptor (GluR1) and the CaMKII. These mice also exhibit significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased number of perforated synapses and larger area of postsynaptic densities revealed by TEM imaging, all consistent with an impaired synaptic function. Taken together, our results demonstrate that the absence of galectin-4 induces synaptic dysfunctions and memory impairment, which correlate with changes in gut microbial composition, suggesting that variations in the endogenous gut microbiota may cause or contribute to such neurological pathologies, even in the absence of pathogenic infections.