Around 2/3 chronic pain patients suffer from memory deficits and underlying mechanisms are unclear. We have shown that over-expression of TNF-αproduced by spared nerve injury (SNI) leads to both neuropathic pain and impairment of short-term memory (Ren, et al., 2011). In the present work with whole-cell patch-clamp electrophysiology and a single-neuron staining by an intracellular injection of biocytin for morphological analysis, we found that SNI reduced the synaptic connection and NMDA receptor current in hippocampal CA1 pyramidal neurons but increased them in NK-1-positive projection neurons in superficial spinal dorsal horn, and the effect was prevented by genetic deletion of TNFR1. TNF-α mimicked the effect of SNI in cultured hippocampal and spinal cord slices. Mechanistically, brain derived neurotrophic factor (BDNF), which is critical for synaptic formation and plasticity, was down-regulated in hippocampus but up-regulated in spinal dorsal horn following SNI. TNF-α also has the similar effect on BDNF expression in cultured hippocampal and spinal cord slices. Thus, the differential change in synaptic structure and function in hippocampus and in spinal dorsal horn may underlie chronic pain and the memory deficits following peripheral nerve injury. The opposite regulation of BDNF by TNF-αmay be critical for pathological process.