Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory

Abstract

Mood disorders are associated with regional brain abnormalities, including reductions in glial cell and neuron number, glutamatergic irregularities, and differential patterns of brain activation. Because astrocytes are modulators of neuronal activity and are important in trafficking the excitatory neurotransmitter glutamate, it is possible that these pathologies are interrelated and contribute to some of the behavioral signs that characterize depression and related disorders. We tested this hypothesis by determining whether depressive-like signs were induced by blocking central astrocytic glutamate uptake with the astrocytic glutamate transporter (GLT-1) inhibitor, dihydrokainic acid (DHK), in behavioral tests that quantify aspects of mood, including reward and euthymia/dysthymia: intracranial self-stimulation (ICSS) and place conditioning. We found that DHK elevated ICSS thresholds, a depressive-like effect that could reflect reduced sensitivity to reward (anhedonia) or increased aversion (dysphoria). However, DHK treatment did not establish conditioned place aversions, suggesting that this treatment does not induce dysphoria. To identify the brain regions mediating the behavioral effects of DHK, we examined c-Fos expression in areas implicated in motivation and emotion. DHK increased c-Fos expression in many of these regions. The dentate gyrus of the hippocampus was robustly activated, which led us to explore whether DHK alters hippocampal learning. DHK impaired spatial memory in the MWM. These findings identify disruption of astrocyte glutamate uptake as one component of the complex circuits that mediate anhedonia and cognitive impairment, both of which are common symptoms of depression. These finding may have implications for the etiology of depression and other disorders that share the features of anhedonia and cognitive impairment.

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

“…Decreased Max Rates can be the result of decreased hedonic value of stimulation (Do Carmo et al, 2009) or reduced performance ability (Carlezon and Chartoff, 2007). The time-course of these effects are consistent with our previous findings using central (Bechtholt-Gompf et al, 2010) or intra-cortical infusions of DHK (John et al, 2012).…”

“…We have previously demonstrated that central infusion of the GLT-1 inhibitor dihydrokainic acid (DHK) produces depressive-like symptoms in rats and induces c-Fos expression in a number of limbic regions, including the central amygdala (CEA) (Bechtholt-Gompf et al, 2010). Additional work has further shown that pharmacological blockade of glutamate uptake in the amygdala (Lee et al, 2007) is sufficient to induce depressive-like social behavior in rats.…”

“…We have previously reported that ICV or intra-PFC DHK is capable of increasing intracranial selfstimulation (ICSS) thresholds and latency to begin drinking sucrose, suggesting that both central and region-specific increases in glutamate can induce anhedonic-like symptoms in rats (Bechtholt-Gompf et al, 2010;John et al, 2012). Here, we used ICSS as a measure of motivation and anhedonia (Carlezon and Chartoff, 2007) to determine whether intra-CEA DHK is sufficient to replicate the anhedonic-like effects we observed previously with ICV infusion.…”

“…DHK does not bind to AMPA/kainite or other glutamate receptors with significant affinity (Johnston et al, 1979), indicating selectivity for GLT-1. Doses of DHK were derived from preliminary studies and previously published behavioral data (Lee et al, 2007;Bechtholt-Gompf et al, 2010;John et al, 2012). DHK was dissolved in phosphate-buffered saline (pH 7.4) as previously reported (Lee et al, 2007).…”

“…The rats were trained on a fixed-ratio-one schedule of reinforcement to obtain brain stimulation as previously described (Carlezon and Chartoff, 2007;Bechtholt-Gompf et al, 2010;John et al, 2012). Briefly, rats were trained to lever press for a 0.5-s pulse train.…”