Abstract
Rationale
GLT-1 is the major glutamate transporter in the brain and is expressed predominantly in astrocytes but is also present in excitatory axon terminals. To understand the functional significance of GLT-1 expressed in neurons, we generated a conditional GLT-1 knockout mouse and inactivated GLT-1 in neurons using Cre-recombinase expressed under the synapsin 1 promoter, (synGLT-1 KO).
Objectives
Abnormalities of glutamate homeostasis have been shown to affect hippocampal-related behaviors including learning and memory as well as responses to drugs of abuse. Here, we asked whether deletion of GLT-1 specifically from neurons would affect behaviors that assessed locomotor activity, cognitive function, sensorimotor gating, social interaction, as well as amphetamine-stimulated locomotor activity.
Methods/results
We found that the neuronal GLT-1 KO mice performed similarly to littermate controls in the behavioral tests we studied. Although performance in open field testing was normal, the acute locomotor response to amphetamine was significantly blunted in the synGLT-1 KO (40% of control). We found no change in amphetamine-stimulated extracellular dopamine in the medial shell of the nucleus accumbens, no change in electrically stimulated or amphetamine-induced dopamine release, and no change in dopamine tissue content.
Conclusions
These results support the view that GLT-1 expression in neurons is required for amphetamine-induced behavioral activation, and suggest that this phenotype is not produced through a change in dopamine uptake or release. Although GLT-1 is highly expressed in neurons in the CA3 region of the hippocampus, the tests used in this study were not able to detect a behavioral phenotype referable to hippocampal dysfunction.
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Abbreviations
- AMP:
-
Amphetamine
- SynCre:
-
Synapsin 1-cre
- AUC:
-
Area under the curve
- PPI:
-
Prepulse inhibition of startle
- NAc:
-
Nucleus accumbens
- dSTR:
-
Dorsal striatum
- DA:
-
Dopamine
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Acknowledgements
The authors wish to acknowledge Nick Andrews and Georgia Gunner of the Neurodevelopmental Behavioral Core at Boston Children‟s Hospital for technical assistance with behavioral experiments. The authors would also like to acknowledge Kush Kapur for statistical consultation.
Funding
This work was supported by NIH grants NS066019, NS075222, MH104318, DA031734, HD018655, and by the Tommy Fuss Fund. KF was supported by T32 NS007473.
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Dr. Bechtholt contributed to this article as an employee of McLean Hospital. The views expressed here are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government.
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Fischer, K.D., Houston, A.C.W., Desai, R.I. et al. Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine. Psychopharmacology 235, 1371–1387 (2018). https://doi.org/10.1007/s00213-018-4848-1
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DOI: https://doi.org/10.1007/s00213-018-4848-1