Astrocytic
glutamate transporter 1 (GLT-1) is responsible for the majority of extracellular
glutamate clearance and is essential for preventing excitotoxicity in the brain. Up-regulation of GLT-1 shows benefit effect on
ischemia-induced neuronal damage. In present study, we examined the effect of
histamine, a
neurotransmitter or
neuromodulator, on GLT-1 expression and function. In acute hippocampal slices,
histamine selectively increased GLT-1 expression independent of neuronal activities. Similar up-regulation of GLT-1 was also observed after
histamine treatment in pure cultured astrocytes, which was abolished by
H1 receptor antagonist or PKC inhibitor. Cell surface biotinylation and whole-cell patch recordings of
glutamate transporter current confirmed the up-regulation of functional GLT-1 following
histamine exposure.
Histamine treatment decreased the extracellular
glutamate content and alleviated neuronal cell death induced by exogenous
glutamate challenge. Moreover, we found a significant
neuroprotective effect of
histamine in brain slices after
oxygen-
glucose deprivation (OGD). In addition,
histidine, the precursor of
histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1 in adult rats subjected to
middle cerebral artery occlusion (MCAO). These
neuroprotective effects of
histamine/
histidine were blocked by GLT-1 specific inhibitor
dihydrokainate or
H1 receptor antagonist. In summary, our results suggest that
histamine up-regulates GLT-1 expression and function via astrocytic
H1 receptors, thus resulting in neuroprotection against excitotoxicity and ischemic injury.