Blocking the BK channel impedes acquisition of trace eyeblink conditioning

Abstract

Big-K+ conductance (BK)-channel mediated fast afterhyperpolarizations (AHPs) following action potentials are reduced after eyeblink conditioning. Blocking BK channels with paxilline increases evoked firing frequency in vitro and spontaneous pyramidal activity in vivo. To examine how increased excitability after BK-channel blockade affects learning, rats received bilateral infusions of paxilline, saline, or nothing into hippocampal CA1 prior to trace eyeblink conditioning. The drug group was slower to acquire the task, but learning was not completely impaired. This suggests that nonspecific increases in excitability and baseline neuronal firing rates caused by in vivo blockade of the BK channel may disrupt correct processing of inputs, thereby impairing hippocampus-dependent learning.Learning and increased neuronal intrinsic excitability are strongly correlated, although a causal relationship has not yet been definitively established (Disterhoft and Oh 2006). One of the mechanisms of increased excitability is through reduction of potassium currents, which cause afterhyperpolarizations (AHP). Afterhyperpolarizations in pyramidal cells can be divided into three categories based upon their timing and duration. The fast AHP lasts only 2-5 ms, follows the depolarizing phase of individual action potentials, and is mediated largely by the big-K + conductance (BK) channel. The post-burst AHP has a medium (50-100 ms) and a slow (1-2 s) component, and follows trains or bursts of action potentials. The medium AHP is carried by apamin sensitive small-K + conductance (SK) channels, but the channel(s), which carry the slow AHP, are still unknown (Storm 1987;Disterhoft and Oh 2006).Learning-related reductions in the post-burst AHP are well documented (for review see Disterhoft and Oh 2006). Additionally, pharmacological modulators of the post-burst AHP alter learning in an expected manner-compounds that reduce the AHP improve learning (galantamine [Simon et al. 2004] and nimodopine [Deyo et al. 1989]). Learning-related reductions of the fast AHP are also seen in prefrontal cortex pyramidal neurons after extinction of fear conditioning (Santini et al. 2008) and in CA1 hippocampal pyramidal neurons after learning trace eyeblink conditioning (tEBC) (Matthews et al. 2008). In vitro whole-cell recordings show that blocking the BK channel with either paxilline or iberiotoxin increases the firing rate to a step current injection (Nelson et al. 2003). Likewise, injection of paxilline into the hippocampus increases the in vivo spontaneous firing frequency of hippocampal CA1 neurons of awake freely moving rats up to 2.5-fold over saline injections (Matthews et al. 2008), indicating that the BK-mediated fast AHP plays an important role in intrinsic excitability. The current study was undertaken to determine whether pharmacologically reducing the fast AHP during training would improve trace eyeblink conditioning.Experimental subjects were 3-to 4-mo old Fisher 344 X Brown Norway F1-hybrid rats. Animals were housed in pairs, in a climate-con...

Increasing SK2 channel activity impairs associative learning

“…to the dorsal hippocampus (Matthews and Disterhoft 2009). If a spherical volume of diffusion is assumed, then a compound will diffuse and occupy about 0.015 cm 3 (or ϳ15 L) of space.…”

“…Guide cannulae, made of 26-gauge stainless steel tubing, were bilaterally implanted in the dorsal hippocampus (3.6 mm posterior and 2.0 mm lateral from bregma, 1.9 mm below the dura) and cemented in place with dental acrylic. A previous report using the same stereotaxic coordinates demonstrated that the diffusion of 1 L of ibotenic acid injected into the dorsal CA1 region via guide cannulae was limited to the dorsal hippocampus (Matthews and Disterhoft 2009). Although not identical in structure, the spread of NS309 should be similar to that observed with ibotenic acid and be limited to the dorsal hippocampus.…”

“…Surgeries to implant a cannula for drug infusion and, in close spatial proximity, a fourtetrode array for unit recordings in the left dorsal CA1 region were performed using previously published methods (Matthews and Disterhoft 2009) and after the rats were anesthetized with a ketamine and xylazine (0.87 mg/kg and 0.13 mg/kg, respectively; ip) mixture, supplemented as necessary during the surgery. The cannula was implanted at 4.8 mm posterior, 3.0 mm lateral from bregma, and 1.9 mm ventral from pia.…”

Hypoxia. 4. Hypoxia and ion channel function

“…It has been shown recently that pharmacological inactivation of K Ca channels leads to learning impairment (143), and deficits in learned behavior have also been described in rodents after 14 days of IH (243). It is perhaps not surprising then, that exposure of adult rat hippocampal neurons to IH for several days decreased the activity of K Ca channels (219,220).…”

SGK3 Sensitivity of Large-Conductance Ca²⁺-Activated K⁺ Channel

“…They are involved in motor coordination [59], learning and memory [28,[60][61][62], circadian rhythm [63][64][65][66], regulation of respiration [67][68][69], hearing [70], and pain [71][72][73][74]. BK channels confer neuroprotection [75][76][77][78].…”