Inhibition of Post-Synaptic Kv7/KCNQ/M Channels Facilitates Long-Term Potentiation in the Hippocampus

Activation of muscarinic acetylcholine receptors (mAChR) facilitates the induction of synaptic plasticity and enhances cognitive function. In the hippocampus, M1 mAChR on CA1 pyramidal cells inhibit both small conductance Ca2+-activated KCa2 potassium channels and voltage-activated Kv7 potassium channels. Inhibition of KCa2 channels facilitates long-term potentiation (LTP) by enhancing Ca2+calcium influx through postsynaptic NMDA receptors (NMDAR). Inhibition of Kv7 channels is also reported to facilitate LTP but the mechanism of action is unclear. Here, we show that inhibition of Kv7 channels with XE-991 facilitated LTP induced by theta burst pairing at Schaffer collateral commissural synapses in rat hippocampal slices. Similarly, negating Kv7 channel conductance using dynamic clamp methodologies also facilitated LTP. Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation. Instead, Kv7 channel inhibition increased the amplitude and duration of the after-depolarisation following a burst of action potentials. Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp. These data reveal that Kv7 channel inhibition promotes NMDAR opening during LTP induction by enhancing depolarisation during and after bursts of postsynaptic action potentials. Thus, during the induction of LTP M1 mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels

Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction

Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leukocytes into the CNS, only few studies describe chemokine expression in neurons. Nevertheless, the expression of neuronal chemokines and the corresponding chemokine receptors in CNS cells under physiological and pathological conditions indicates that neuronal chemokines contribute to CNS cell interaction. In this study, we review recent studies describing neuronal chemokine expression and discuss potential roles of neuronal chemokines in neuron–astrocyte, neuron–microglia, and neuron–neuron interaction

Scopolamine Administration Modulates Muscarinic, Nicotinic and NMDA Receptor Systems

Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1) has been reported. We hypothesized that levels of other cholinergic brain receptors as the nicotinic receptors and the N-methyl-D-aspartate (NMDA) receptor, known to be involved in memory formation, would be modified by scopolamine administration

Simplified compartmental models of CA1 pyramidal cells of theta-modulated inhibition effects on spike timing-dependent plasticity

Spike timing-dependent plasticity (STDP) is a causal form of Hebb’s law of synaptic plasticity, where the precise timing of the presynaptic and postsynaptic action potentials determines the sign and magnitude of synaptic modifications (Bell et al., 1997; Bi and Poo, 1998; Magee and Johnston, 1997; Markram et al., 1997; Debanne et al., 1998; Sjostrom et al., 2001; Yao and Dan, 2001; Zhang et al., 1998). In their pioneering study, Bi and Poo (1998) showed that the shape of the STDP curve in the in-vitro hippocampal network has an asymmetric shape with the largest LTP/LTD value at Δτ = tpost - tpre = +/-10 ms, respectively. New experimental evidence has shown that the STDP asymmetry can sometimes change with the target and the location of the synapse (Tzounopoulos et al., 2004; Froemke et al., 2005; Letzkus et al., 2006; Caporale and Dan, 2009) and can be dynamically regulated by the activity of adjacent synapses (Harvey and Svoboda et al., 2007; Caporale and Dan, 2009) or by the action of neuromodulators (Seol et al., 2007; Caporale and Dan, 2009). Nishiyama and colleagues (2000) reported that "...the profile of STDP induced in the hippocampal CA1 network with inhibitory interneurons is symmetrical for the relative timing of pre- and postsynaptic activation". Optical imaging studies in CA1 revealed that the shape of the STDP curve depends on the location on the stratum radiatum (SR) dendrite. A symmetric STDP profile was observed in the proximal-to-the-soma SR dendrite and an asymmetric STDP profile in the distal-to-the-soma one (Tsukada et al., 2005; Aihara et al., 2007). They suggested that this change in the shape of the STDP curve (i.e. from symmetry to asymmetry and vice versa) may be due to inhibition in the proximal SR dendrites (Tsukada et al., 2005). The functional consequences of such a change in the STDP temporal kernel dynamics are of great importance in neural network dynamics. A symmetrical STDP profile with short temporal windows may serve as a coincidence detector between the incoming inputs and plays a functional role in heteroassociation of memories (Cutsuridis et al., 2010). On the other hand an asymmetric STDP profile with broad temporal windows may play a role in chunking of ordered items in sequence learning (Hayashi and Igarashi, 2009). Up-to-now very few studies (Cutsuridis, 2010, 2011, 2012, 2013) have investigated the inhibitory factors (frequency, strength, timing, etc.) that are responsible for such a change in the shape in the STDP temporal kernel and the conditions under which a transition from asymmetrical STDP kernel to a symmetrical STDP kernel is possible. In this chapter, I will present two simplified compartmental models of CA1 pyramidal cells in order to investigate the role of theta-modulated inhibition on the shape, sign and magnitude of the STDP kernel in CA1 pyramidal cell proximal dendrites

Laser capture microdissection and cDNA array analysis of endometrium identify CCL16 and CCL21 as epithelial-derived inflammatory mediators associated with endometriosis

<p>Abstract</p> <p>Background</p> <p>Understanding the pathophysiology of chemokine secretion in endometriosis may offer a novel area of therapeutic intervention. This study aimed to identify chemokines differentially expressed in epithelial glands in eutopic endometrium from normal women and those with endometriosis, and to establish the expression profiles of key chemokines in endometriotic lesions.</p> <p>Methods</p> <p>Laser capture microdissection isolated epithelial glands from endometrial eutopic tissue from women with and without endometriosis in the mid-secretory phase of their menstrual cycles. Gene profiling of the excised glands used a human chemokine and receptor cDNA array. Selected chemokines were further examined using real-time PCR and immunohistochemistry.</p> <p>Results</p> <p>22 chemokine/receptor genes were upregulated and two downregulated in pooled endometrial epithelium of women with endometriosis compared with controls. CCL16 and CCL21 mRNA was confirmed as elevated in some women with endometriosis compared to controls on individual samples. Immunoreactive CCL16 and CCL21 were predominantly confined to glands in eutopic and ectopic endometrium: leukocytes also stained. Immunoreactive CCL16 was overall higher in glands in ectopic vs. eutopic endometrium from the same woman (P < 0.05). Staining for CCL16 and CCL21 was highly correlated in individual tissues.</p> <p>Conclusion</p> <p>This study provides novel candidate molecules and suggests a potential local role for CCL16 and CCL21 as mediators contributing to the inflammatory events associated with endometriosis.</p