The mRNA levels of NKCC1, an inwardly directed Na
+
, K
+
-2Cl
−
cotransporter that facilitates the accumulation of intracellular Cl
−
, and of KCC2, an outwardly directed K
+
-Cl
−
cotransporter that extrudes Cl
−
, were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients. Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl
−
transporters in the TLE subiculum. In parallel experiments, cell membranes isolated from the same TLE-associated brain regions were injected into
Xenopus
oocytes that rapidly incorporated human GABA
A
receptors into their surface membrane. The GABA currents elicited in oocytes injected with membranes from the subiculum had a more depolarized reversal potential (
E
GABA
) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10°C shifted the GABA-current
E
GABA
more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the
E
GABA
of TL neocortex-injected oocytes. We conclude that the anomalous expression of both Cl
−
transporters, KCC1 and NKCC2, in TLE hippocampal subiculum probably causes altered Cl
−
transport in the “epileptic” neurons, as revealed in the microtransplanted
Xenopus
oocytes, and renders GABA aberrantly “exciting,” a feature that may contribute to the precipitation of epileptic seizures.
SummaryThe Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is involved in many cellular processes, including cell growth and differentiation, immune functions and cancer. It is activated by various cytokines, growth factors, and protein tyrosine kinases (PTKs) and regulates the transcription of many genes. Of the four JAK isoforms and seven STAT isoforms known, JAK2 and STAT3 are highly expressed in the brain where they are present in the postsynaptic density (PSD). Here, we demonstrate a new neuronal function for the JAK/STAT pathway. Using a variety of complementary approaches, we show that the JAK/STAT pathway plays an essential role in the induction of NMDA-receptor dependent long-term depression (NMDAR-LTD) in the hippocampus. Therefore, in addition to established roles in cytokine signaling, the JAK/STAT pathway is involved in synaptic plasticity in the brain.
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