No abstract

The K ϩ channel pore-forming subunit Kv4.3 is expressed in a subset of nonpeptidergic nociceptors within the dorsal root ganglion (DRG), and knockdown of Kv4.3 selectively induces mechanical hypersensitivity, a major symptom of neuropathic pain. K ϩ channel modulatory subunits KChIP1, KChIP2, and DPP10 are coexpressed in Kv4.3 ϩ DRG neurons, but whether they participate in Kv4.3-mediated pain control is unknown. Here, we show the existence of a Kv4.3/KChIP1/KChIP2/DPP10 complex (abbreviated as the Kv4 complex) in the endoplasmic reticulum and cell surface of DRG neurons. After intrathecal injection of a gene-specific antisense oligodeoxynucleotide to knock down the expression of each component in the Kv4 complex, mechanical hypersensitivity develops in the hindlimbs of rats in parallel with a reduction in all components in the lumbar DRGs. Electrophysiological data further indicate that the excitability of nonpeptidergic nociceptors is enhanced. The expression of all Kv4 complex components in DRG neurons is downregulated following spinal nerve ligation (SNL). To rescue Kv4 complex downregulation, cDNA constructs encoding Kv4.3, KChIP1, and DPP10 were transfected into the injured DRGs (defined as DRGs with injured spinal nerves) of living SNL rats. SNL-evoked mechanical hypersensitivity was attenuated, accompanied by a partial recovery of Kv4.3, KChIP1, and DPP10 surface levels in the injured DRGs. By showing an interdependent regulation among components in the Kv4 complex, this study demonstrates that K ϩ channel modulatory subunits KChIP1, KChIP2, and DPP10 participate in Kv4.3-mediated mechanical pain control. Thus, these modulatory subunits could be potential drug targets for neuropathic pain.

No abstract

Hebbian plasticity, widely regarded as the cellular mechanism for learning and memory, posits that the formation of a long-lasting memory requires a tight temporal co-activation of pre- and postsynaptic inputs encoding that memory. Here we demonstrate that forms of synaptic manipulation deviating from Hebbian rules can produce a long-lasting memory. To this end, we optogenetically manipulate independently two inputs to the lateral amygdala (LA), a region known to mediate fear memories. We focused on the association of one input to the LA with a foot shock, which does not form a detectable memory. This experience can be converted to a long-lasting memory by induction of synaptic potentiation of the input alone, delivered minutes before, minutes after, or even 24 hours later. Notably, a similar conversion to a long-lasting memory is achieved by potentiating an independent input to the LA delivered minutes, but not 24 hours after the experience. Surprisingly, in a non-associative conditioning paradigm, strong stimulation of an independent input uncovers the aversive memory of the shock. Our results indicate that different forms of plasticity can proactively as well as retroactively impact the persistence of memories, an effect with computational and behavioral implications.