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. 2010 Sep;35(10):2049-59.
doi: 10.1038/npp.2010.74. Epub 2010 Jun 9.

Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory

Anita J Bechtholt-Gompf  1 , Hali V Walther, Martha A Adams, William A Carlezon Jr, Dost Ongür, Bruce M Cohen
Affiliations

Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory

Anita J Bechtholt-Gompf et al. Neuropsychopharmacology. 2010 Sep.

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.

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Figures

Figure 1
Figure 1
Location of the 15 areas counted for c-Fos immunoreactivity indicated on atlas representations of the rat brain (Figures 12, 19, 56, 59, 94, 115 in reference Paxinos and Watson, 2004). Abbreviations are defined in Table 1.
Figure 2
Figure 2
Effect of ICV DHK (12.5, 25.0, or 50.0 nmol) on ICSS thresholds over 45 min (left panel) and within the first 15 min (right panel) after infusion. Follow-up comparisons showed that the effects of DHK were short in duration and dose-dependent. Significant effects were observed during the first 15 min after DHK infusion (right panel) and increasing doses of DHK yielded greater thresholds. *: Significantly different from the vehicle group. Time × dose interaction: p<0.05. †: Significantly different from the 50.0-nmol group. One symbol: p<0.05; two symbols: p<0.01 (n=7).
Figure 3
Figure 3
Effect of ICV DHK (12.5, 25.0, or 50.0 nmol) on ICSS maximum response rate across three passes (left panel) and within the first 15 min (right panel). A significant main effect of time was detected, showing an increase in the maximum response rate over time. However, the time and the DHK dose did not interact. Main effect of time: p<0.05 (n=7).
Figure 4
Figure 4
ICSS rate–frequency functions from a representative rat at baseline and after treatment with 50 nmol DHK. Changes in motivation are indicated by lateral shifts of the frequency response curve. Shifts to the right of this frequency response curve indicate that higher frequencies of brain stimulation are required to support lever pressing, suggesting depressed-like mood with an anhedonic or dysphoric state. Shifts to the left indicate that lower frequencies are required to maintain responding, suggesting an elevated mood with a state of enhanced reward. Vertical shifts in the frequency response curve can also be indicative of changes in motivation; however, it is difficult to distinguish these effects from effects on performance capacity. These curves show that DHK caused both a downward and a rightward shift in the rate–frequency functions.
Figure 5
Figure 5
Effect of ICV DHK (25.0 or 50.0 nmol) on average aversion scores. Neither dose of DHK that increased ICSS thresholds was sufficient to induce conditioned place aversion (n=8–9 per group).
Figure 6
Figure 6
Effect of ICV DHK (25.0 or 50.0 nmol) on the average distance traveled in cm within 5-min intervals for the 30-min test with the lights off (top panel) or lights on (bottom panel). Inset: Data pooled into two 15-min intervals; timing corresponding to the effects observed in ICSS (n=8–10 per group).
Figure 7
Figure 7
Example photomicrographs for the effects of PBS or 50.0 nmol of DHK on c-Fos expression in the dDG. The left side is medial. The bar graphs show the mean number of c-Fos-positive cells in the dDG after treatment with varying doses of DHK. *: Significantly different from the vehicle group; †: significantly different from the 25.0-nmol group.
Figure 8
Figure 8
Example photomicrographs for the effects of PBS or 50.0 nmol of DHK on c-Fos expression in the IL at × 10 (left panels) and × 20 (right panels) magnification. The left side is medial. Outlines in the left panels indicate the area magnified in the right panels. The bar graphs show the mean number of c-Fos-positive cells in the IL after treatment with varying doses of DHK. *: significantly different from the vehicle group; †: significantly different from the 25.0-nmol group.
Figure 9
Figure 9
A line graph showing drug-free acquisition of the MWM task expressed as the average distance traveled (cm) to reach the platform during each of seven training days (top panel). The bottom panels show the effects of DHK during the post-training probe test on velocity (left), mean distance from the platform (middle), and the percent of time spent in the target quadrant (right). DHK significantly increased swim velocity and the mean distance from the platform, but decreased the time spent in the target quadrant. *: Significantly different from the vehicle group (n=9–10 per group).
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