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  • Increasing evidence has shown that blockade of glutamate upt

    2022-01-19

    Increasing evidence has SZL P1-41 shown that blockade of glutamate uptake leads to aberrant behavioral consequences. For example, intracerebroventricular (i.c.v) injection or microinjection of the GLT-1 inhibitor, dihydrokainic SZL P1-41 (DHK), into the prefrontal cortex induces anhedonia [8,9]. Microinjection of DHK into the amygdala central nucleus produces both depressive-like and anxiety behaviors [10]. Intrathecal or i.c.v. administration of a non-selective glutamate transporters inhibitor L-trans-PDC induces an inhibitory effect on the micturition reflex [11]. GLT1 complex expression levels are paralleling memory training [12], and blockade of glutamate uptake affects synaptic transmission and plasticity [[13], [14], [15]]. However, the effect of GLT1 blockade on learning and memory still receives little attention. The novel object recognition (NOR) task is a learning and memory paradigm in which mice or rats show an innate preference for novelty such that they will spend more time exploring the novel object once they recognize the familiar one [16]. Currently, this paradigm is widely used to evaluate recognition memory in rodents [17]. In the present study, we firstly determined the effect of unilateral i.c.v. injection of DHK on short-term NOR memory performance in mice. Then, we determine whether unilateral i.c.v. injection of DHK affects the acquisition, consolidation and retrieval of long-term NOR memory.
    Material and methods
    Results
    Discussion In the present study, we explored the effects of unilateral i.c.v. injection of DHK on NOR memory performance, a hippocampal-dependent task [17], in mice. We found that DHK at 6.25 nmol impaired both short-term NOR memory performance in experiment 1, and the acquisition, consolidation and retrieval of long-term NOR memory in experiment 2, 3 and 4, respectively. Importantly, DHK at 6.25 nmol did not affect the numbers of crossings and total object exploratory time 0.5, 2 and 24.5 h after drug injection, suggesting that DHK-induced NOR memory performance impairment is not due to its effects on nonspecific responses such as exploratory behavior and locomotor activity. In experiment 1, DHK at higher doses (12.5 and 25 nmol) significantly decreased the numbers of crossings and total exploratory time during the sampling but not test sessions, suggesting that DHK at higher doses produces an acute impairment in locomotor activity and exploratory behavior. This impairment might be due to acute excitotoxicity induced by DHK as selective inhibition of GLT1 using chronic antisense oligonucleotide administration leads to excitotoxicity and a progressive paralysis [22]. A previous study reported that i.c.v. injection of DHK at the doses of 25 and 50 nmol did not affect locomotor activity during a 30-min period immediately after drug administration in rats [8]. A difference in animal species (mouse versus rat) may account for the inconsistent data. A large number of studies suggests that these exits a critical time window, usually 1–6 h post-training, only during which pharmacological manipulation or sleep deprivation is proved to be effective on memory consolidation [21,23]. In experiment 3, we observed that DHK injection immediately but not 6 h post-sampling impaired long-term NOR memory performance, suggesting a time-dependent effect of DHK on NOR memory consolidation. This differential effect is consistent with a previous finding that the protein synthesis inhibitor anisomycin administrated immediately but not 6 h after sampling impairs NOR memory consolidation [21]. Additionally, DHK injection 6 h post-sampling did not impaired NOR memory performance, further suggesting that DHK-induced NOR memory performance impairment is not the result of nonspecific responses. Accumulated data suggest that multiple brain regions such as the hippocampus and prefrontal cortex are critically involved in NOR memory [17,24]. GLT1 is highly expressed in the hippocampus and pivotal for maintaining glutamate homeostasis [12,22]. Disruption of glutamate homeostasis is usually associated with hippocampal-dependent learning and memory impairments under normal physiological condition. For example, pharmacological upregulation of GLT-1 impairs hippocampal synaptic transmission and plasticity, and learning in rats [[25], [26], [27]]. Pharmacological inhibition of GLT-1 via DHK disrupts hippocampal-dependent spatial memory in the Morris water maze task in rats [8]. The current results indicate that DHK impairs NOR memory performance in mice. Presumably, a dysfunction of glutamate uptake in the hippocampus might be related to NOR memory performance impairment induced by DHK. Furthermore, previous studies have shown that i.c.v. injection or infusion of DHK into the prefrontal cortex or the amygdala produces anhedonia and impairs spatial memory [[8], [9], [10]]. These observations imply that i.c.v. injection of DHK might result in a cumulative global disruption of glutamate uptake, which possibly affect non-memory circuits and impair memory performance overall. This issue needs to be clarified in future studies.