The 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 thousands of 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).However, the cellular and molecular mechanisms by which the JAK/STAT pathway is involved in synaptic function is unknown.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.We find that pharmacological inhibition of JAK blocks the induction of NMDAR-LTD at CA1 synapses in the hippocampus.This effect is highly selective since the same treatment that completely prevents the induction of NMDAR-LTD has no effect on LTP, depotentiation or LTD induced by the activation of mGluRs.We find that the JAK2 isoform is enriched at synapses and knockdown of JAK2 also blocks the induction of NMDAR-LTD.Furthermore, activation of NMDARs, either pharmacologically or by low frequency stimulation (LFS), causes a transient activation of JAK2.Finally, we present evidence that the effects of JAK2 in NMDAR-LTD are mediated via STAT3.Thus, LFS causes activation and nuclear translocation of STAT3 and pharmacological inhibition of STAT3 also blocks the induction of NMDAR-LTD.Therefore,it can be concluded that the JAK/STAT pathway has a key role in synaptic plasticity in the CNS.