Blockade of IP₃-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory

Abstract

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP 3 -PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP 3 receptor (IP 3 R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP 3 R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP 3 R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.The prefrontal cortex coordinates and controls cognitive and emotional processes utilizing appropriate judgment, flexibility, and attention (Goldman-Rakic 1995a,b;Fuster 2000). A hallmark operation of the prefrontal cortex is working memory (WM)-the ability to internally maintain information in the absence of external representation. Debilitating deficits in WM and prefrontal function are associated with numerous conditions including schizophrenia, attention deficit hyperactivity disorder, aging, and stress (Goldman-Rakic 1992;Arnsten 1993;Goldman-Rakic and Selemon 1997;Ramos et al. 2003;Birnbaum et al. 2004). Elucidating mechanisms of cognitive impairment will contribute to identification and development of novel therapeutic targets for treatment of prefrontal decline.Local excitatory circuits are believed to underlie WM operations (Goldman-Rakic 1995a,b) and disruption in prefrontal neuronal activity is associated with WM impairment (GoldmanRakic 1995a,b). Disruptions can arise from altered catecholamine release within the prefrontal cortex. High levels of norepinephrine release, which typically follow a stressor (Rossetti et al. 1990;Finlay et al. 1995), impair WM performance by binding G qcoupled ␣1-adrenoceptors, leading to activation of the phosphatidylinositol (PI) cascade (Garcia-Sainz 1993;Birnbaum et al. 1999Birnbaum et al. , 2004. In the PI pathway, phospholipase C cleaves the phospholipid phosphatidylinositol bisphosphate (PIP 2 ) to generate membrane-bound diacylglycerol (DAG) and diffusible inositol 1, 4, 5-trisphosphate (IP 3 (Kohler et al. 1996). SK channels influence firing frequency by modulating after-hyperpolarization (Pedarzani et al. 2005;Sah 1996) and are therefore positioned to impact the network functions of the prefrontal cortex, which rely on highly synchronized sequences of firing. A recent study by Hagenston et al. (2007) indicates that IP 3 R-SK channel signaling regulates prefrontal neuron firing. IP 3 -mediated release of Ca 2+ resulted in hyperpolarization of layer V pyramidal neurons in rat medial prefrontal slices (Hagenston et al. 2007). This hyperpolarization was reversed by application of the SK channel blocker, apamin (Hagenston et al. 2007), suggesting a mechanistic role of SK channels in prefrontal dysfunction.This study sought to clarify whether IP 3 R sign...

Deviant Ryanodine Receptor-Mediated Calcium Release Resets Synaptic Homeostasis in Presymptomatic 3xTg-AD Mice

“…These findings are consistent with RyR-evoked calcium release activating postsynaptic calcium-activated K ϩ channels, likely the SK channels, which mediate the medium afterhyperpolarization and suppress membrane excitability (Stutzmann et al, 2006;Brennan et al, 2008). To assess the role of SK channels in synaptic transmission, we compared the I/O function after blocking these channels with 1 M apamin (Fig.…”

“…Likewise, dantrolene did not affect the I/O function in NonTg mice yet significantly increased the I/O function in the 3xTg-AD mice, particularly at higher stimulation intensities. This is consistent with RyRevoked calcium release activating postsynaptic calciumactivated SK channels (Stutzmann et al, 2006;Brennan et al, 2008). In parallel with the effects of dantrolene, blocking the SK channel had little effect on the I/O function in NonTg mice yet increased the I/O function in the 3xTg-AD mice at higher stimulus intensities.…”

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…For example, the decrease in SK channel function following CIE treatment observed in many regions including the OFC would be expected to enhance synaptic efficacy and plasticity. In support of this, results from previous studies show that blocking these channels facilitates LTP and enhances learning and memory (Blank et al, 2003;Brennan et al, 2008;Hammond et al, 2006;Stackman et al, 2002), whereas overexpression of SK channels reduces LTP and impairs hippocampus-, amygdala-, and mPFC-dependent learning tasks. In addition to changes in glutamate receptor expression and function described above, alterations in dendritic Figure 8 Chronic intermittent ethanol (CIE) exposure suppresses the ability of the GlyT1 transport inhibitor sarcosine to reduce spiking in lateral orbitofrontal cortex (lOFC) neurons.…”

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

“…Activation of Ca 2+ -calmodulin-dependent kinase II (CaMKII) and inhibition of the Ca 2+ -activated phosphatase, calcineurin, impair spatial working memory in the rat (Runyan et al 2005;Dash et al 2007). These actions may be mediated, in part, by the opening of small-conductance Ca 2+ -gated potassium channels (SK channels) that suppress neuronal firing (Hagenston et al 2007;Brennan et al 2008). Protein kinase C (PKC) is cooperatively activated by Ca 2+ and DAG.…”