Abstract
Fear extinction correlates with increased infralimbic (IL) neuronal excitability. Since small conductance Ca2+-dependent K+ (SK) channels modulate neuronal excitability and certain types of learning and memory, pharmacological modulation of SK channels could be used to regulate IL excitability and fear extinction. To test this, we first determined the effect of blocking SK channels with apamin on the intrinsic excitability of IL pyramidal neurons in brain slices. In whole-cell patch-clamp recordings, apamin increased the number of spikes evoked by a depolarizing current pulse, increased the firing frequency, and reduced the fast afterhyperpolarizing potential (fAHP) indicating that blockade of SK channels could be used to enhance the intrinsic excitability of IL neurons. Next, we assessed whether SK channels in IL regulate extinction of conditioned fear by infusing apamin into IL of fear conditioned rats prior to extinction training. Apamin infusion did not affect conditioned freezing at the beginning of the extinction session or within-session extinction. However, the following day, apamin-infused rats showed significantly less conditioned freezing. To further examine the importance of SK channels in IL in fear extinction, we assessed the effect of the SK channel activator DCEBIO on IL neuronal excitability and fear extinction. Activation of SK channels with DCEBIO decreased the number of evoked spikes, reduced the firing frequency, and enhanced the fAHP of IL neurons. Infusion of DCEBIO into IL prior to fear extinction impaired recall of fear extinction without affecting acquisition of extinction. Taken together, these findings suggest that SK channels are involved in regulating IL excitability and extinction-induced plasticity. Therefore, SK channels are a potential target for the development of new pharmacological treatments to facilitate extinction in patients suffering from anxiety disorders.
Highlights
Effective retrieval of the fear extinction memory is associated with increased activation of neurons in a specific subdivision of the medial prefrontal cortex, the infralimbic (IL) cortex (Milad and Quirk, 2002, 2012; Holmes et al, 2012)
BLOCKADE OF small conductance Ca2+-dependent K+ (SK) CHANNELS INCREASED THE NUMBER OF EVOKED SPIKES AND BURST FIRING IN IL PYRAMIDAL NEURONS First, we examined whether SK channels modulate the excitability of IL neurons by assessing the effect of the SK channel blocker, apamin, on the intrinsic excitability of IL pyramidal neurons using whole-cell patch-clamp recordings in coronal slices of the medial prefrontal cortex (mPFC)
These results indicate that blocking SK channels increases the intrinsic excitability and burst firing of IL pyramidal neurons
Summary
Effective retrieval of the fear extinction memory is associated with increased activation of neurons in a specific subdivision of the medial prefrontal cortex (mPFC), the infralimbic (IL) cortex (Milad and Quirk, 2002, 2012; Holmes et al, 2012). NMDA, muscarinic, and mGluR5 receptors generate increases in intracellular calcium that can activate small conductance Ca2+-dependent K+ (SK) channels (Sourdet et al, 2003; Faber et al, 2005; Ngo-Anh et al, 2005; Gulledge et al, 2007) resulting in reduced neuronal excitability and afterhyperpolarization potentials (AHP; Bond et al, 2005) Secondary to their calcium-dependence and localization near NMDA receptors, SK channels shunt NMDA receptor currents and can prevent the induction of synaptic plasticity needed for memory formation (Ngo-Anh et al, 2005; Hammond et al, 2006; Stackman et al, 2008; McKay et al, 2012). Inhibiting SK channels in IL could enhance the excitatory actions of NMDA, muscarinic and mGluR5 receptors and facilitate fear extinction-induced plasticity and extinction memory
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