Protein kinase a-mediated suppression of the slow afterhyperpolarizing KCa3.1 current in temporal lobe epilepsy

Brain insults, such as trauma, stroke, anoxia, and status epilepticus (SE), cause multiple changes in synaptic function and intrinsic properties of surviving neurons that may lead to the development of epilepsy. Experimentally, a single SE episode, induced by the convulsant pilocarpine, initiates the development of an epileptic condition resembling human temporal lobe epilepsy (TLE). Principal hippocampal neurons from such epileptic animals display enhanced spike output in response to excitatory stimuli compared with neurons from nonepileptic animals. This enhanced firing is negatively related to the size of the slow afterhyperpolarization (sAHP), which is reduced in the epileptic neurons. The sAHP is an intrinsic neuronal negative feedback mechanism consisting normally of two partially overlapping components produced by disparate mechanisms. One component is generated by activation of Ca ²⁺-gated K + (K_Ca ) channels, likely KCa3.1, consequent to spike Ca ²⁺ influx (the K_Ca-sAHP component). The second component is generated by enhancement of the electrogenic Na+/K+ ATPase (NKA) by spike Na+ influx (NKA-sAHP component). Here we show that the K_Ca-sAHP component is markedly reduced in male rat epileptic neurons, whereas the NKA-sAHP component is not altered. The K_Ca-sAHP reduction is due to the downregulation of KCa3.1 channels, mediated by cAMP-dependent protein kinase A (PKA). This sustained effect can be acutely reversed by applying PKA inhibitors, leading also to normalization of the spike output of epileptic neurons. We propose that the novel “acquired channelopathy” described here, namely, PKA-mediated downregulation of KCa3.1 activity, provides an innovative target for developing new treatments for TLE, hopefully overcoming the pharmacoresistance to traditional drugs.