We previously demonstrated that inactivation of
Rho-kinase by
hydroxyfasudil could impact
N-methyl-d-aspartate (
NMDA) excitatory interneurons in the hippocampus and attenuate the spatial learning and memory dysfunction of rats caused by chronic forebrain hypoperfusion
ischemia. Complementary interactions between the excitatory
neurotransmitter glutamate and the inhibitory
neurotransmitter GABA form the molecular basis of synaptic plasticity and cognitive performance. However, whether the GABAergic inhibitory interneurons are involved in the mechanisms underlying these processes remains unclear. Here, we further examined the role of GABAergic interneurons in the
neuroprotective effect of the
Rho-kinase inhibitor. Chronic forebrain
ischemia was induced in Wistar rats by bilateral common carotid artery occlusion (BCAO). The general synaptic transmission and long-term potentiation (LTP) of hippocampal CA3 neurons were evaluated at 30 days after
sham surgery or BCAO. Real-time PCR and Western blot analyses were conducted to determine the effect of the
Rho-kinase inhibitor
hydroxyfasudil on GABAergic inhibitory interneuron expression and function after
ischemia.
Hydroxyfasudil showed no significant effect on general synaptic transmission, but it could abolish the inhibition of LTP induced by chronic forebrain
ischemia. Moreover, the
mRNA and
protein levels of GABAA and GABAB in three brain regions after
ischemia were markedly decreased, and
hydroxyfasudil could up-regulate all
mRNA and
protein expression levels in these areas except for GABAA
mRNA in the cerebral cortex and striatum. Using phosphorylation
antibodies against specific sites on the GABAA and GABAB receptors, we further demonstrated that
hydroxyfasudil could inhibit GABAergic interneuron phosphorylation triggered by the theta burst stimulation. In summary, our results indicated that the inactivation of
Rho-kinase could enhance GABAA and GABAB expressions by different mechanisms to guarantee the induction of hippocampal LTP, and it could decrease the phosphorylation level of GABAergic inhibitory interneurons to promote the LTP induction rate and magnitude, hence improving the cognitive deficit suffered after chronic forebrain
ischemia.