Maqui berry, inulin and probiotics attenuate ketamine-induced cognitive and hippocampal synaptic alterations in adolescent mice

Dietary interventions targeting the gut–brain axis have emerged as potential strategies to modulate neurodevelopmental vulnerability to pharmacological insults. Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely used in experimental models to induce persistent alterations in cognition and synaptic function when administered during sensitive developmental periods. This study aimed to evaluate whether a synbiotic formulation composed of maqui berry, inulin and probiotics could attenuate hippocampal synaptic and behavioural alterations induced by adolescent ketamine exposure in mice.

Adolescent mice were exposed to ketamine and received supplementation with the synbiotic formulation. Recognition memory was assessed using the novel object recognition test, while investigation time, locomotor activity and anxiety-related behaviour were evaluated to control for non-cognitive behavioural confounders. Synaptic plasticity was examined in hippocampal slices by recording field population spike slope in the dentate gyrus before and after high-frequency stimulation. Electrophysiological recordings were obtained from vehicle plus synbiotic, ketamine plus synbiotic and ketamine groups, with n = 5, n = 7 and n = 5 slices, respectively. Data were analysed using one-way analysis of variance followed by Tukey’s multiple comparisons test, with significance set at p < 0.05.

Ketamine-treated mice showed a significant reduction in the discrimination index in the novel object recognition test compared with vehicle-treated mice (mean difference = 35.38, 95% confidence interval: 11.17 to 59.60, p = 0.0035) and vehicle plus synbiotic mice (mean difference = 36.22, 95% confidence interval: 8.476 to 63.96, p = 0.0088). Mice receiving ketamine plus the synbiotic formulation showed a significantly higher discrimination index than ketamine-treated mice (mean difference = -30.12, 95% confidence interval: -57.86 to -2.378, p = 0.0310). No significant differences were detected between vehicle and vehicle plus synbiotic groups, or between ketamine plus synbiotic and control groups, indicating that synbiotic supplementation attenuated the ketamine-induced recognition memory deficit. In contrast, investigation time did not show significant differences, suggesting that the effect on discrimination index was not explained by altered exploratory drive. No significant differences were observed in locomotor activity or anxiety-related measures in the open field test.

In the dentate gyrus, high-frequency stimulation induced an exaggerated field population spike response in ketamine-treated slices (150.9 ± 3.297; n = 5) compared with vehicle plus synbiotic (108.8 ± 0.6678; n = 5) and ketamine plus synbiotic slices (109.1 ± 0.6791; n = 7). Tukey’s multiple comparisons test showed significant differences between ketamine and vehicle plus synbiotic groups (mean difference = -42.06, 95% confidence interval: -48.99 to -35.13, p < 0.0001) and between ketamine and ketamine plus synbiotic groups (mean difference = -41.77, 95% confidence interval: -48.70 to -34.84, p < 0.0001). No significant difference was detected between vehicle plus synbiotic and ketamine plus synbiotic groups (p = 0.9948).

These preliminary findings suggest that a synbiotic formulation composed of maqui berry, inulin and probiotics attenuates ketamine-induced recognition memory impairment and normalises abnormal hippocampal dentate gyrus synaptic responses induced by adolescent ketamine exposure. Further studies are required to determine the molecular mechanisms and translational relevance of this intervention as a nutritional strategy.

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