Glutamate excitotoxicity has been implicated as the common mechanism underlying neuropsychiartric disorders including epilepsy, schizophrenia, autism, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
Glial glutamate transporter GLT1 plays dominant role in regulating the extracellular glutamate level. The reduced expression of GLT1 has been implicated in brain regions that are damaged in these disorders. To clarify the relationship between excitotoxicity and pathogenesis of these diseases in vivo, we generated brain region-specific GLT1 knockout mice by crossing floxed-GLT1 mouse with Cre lines expressing Cre recombinase in dorsal-telencephalon or diencephalon and brain stem.
Cortex-specific GLT1 knockout pups show spontaneous motor startles followed by a tonic extension of the four limbs associated with running around two weeks of age. Furthermore, degeneration of cortical layer 2/3 neurons and hippocampal pyramidal neurons are observed in the mutants.
On the other hand, mice with deficiency of GLT1 in thalamus and brain stem exhibit lethal spontaneous seizure with no significant cell death. In addition, the mutants exhibit depression-like behaviors.
These results indicate that GLT1 dysfunction in diencephalon and brain stem is associated with spontaneous lethal epileptic seizure and depression-like behaviors, whereas GLT1 in cortex plays a critical role in preventing infantile epilepsy and protecting cortical layer 2/3 and hippocampal pyramidal neurons from excitotoxicity. These region-specific GLT1 KO mice will be useful for understanding the role of excitotoxicity in neuropsychiatric diseases.