Search

Accumulation of beta-amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ-overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aβ 1-42 peptide. Whole cell current clamp recordings were compared between Aβ-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients.

Persistent plastic changes to the intrinsic excitability of neurons have substantial implications for computational processing within the CNS. We have identified and characterized a novel long-lasting form of intrinsic plasticity in hippocampal CA3 pyramidal cells. Although the patterns of action potential firing elicited in this cell population by depolarizing current injections exhibited considerable diversity, practically all cells produced an initial high frequency (>100 Hz) burst of two to five spikes. This burst involved conductances that were responsible for the prominent spike afterdepolarization of CA3 pyramids. Long-lasting changes in the firing behaviour of CA3 cells were produced by conditioning stimuli (CS) consisting of either periods of depolarization in voltage clamp or periods of short (2 or 4 spikes) high frequency (circa 100 Hz) burst firing at 5 or 10 Hz. CS-induced changes included substantial prolongation of the first inter-spike interval and increased spike jitter. Similar CS-induced changes were seen when the test stimulus used to elicit firing resembled a glutamatergic EPSC. In line with this, a long-lasting depression of the ADP was elicited by the same CS that altered firing patterns of CA3 cells. Conditioning-induced changes in both spiking patterns and ADP amplitude were blocked by buffering intracellular Ca2+ with BAPTA. Furthermore, the Kv7 channel blocker XE991, a cognitive enhancer, both enhanced the ADP and completely eliminated its conditioning-induced depression. These findings indicate that a persistent enhancement of Kv7 channels, following a transient increase in cytoplasmic Ca2+, results in a prolonged depression of the ADP in CA3 pyramidal neurones.

Background and purpose: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. Experimental approach: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. Key results: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. Conclusions and implications: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR. British Journal of Pharmacology (2008) 154, 1104–1115; doi:10.1038/bjp.2008.152; published online 5 May 2008

In the mammalian central nervous system, GABA B receptors mediate slow pre- and postsynaptic inhibition. Using rat hippocampal slices we investigated the role of synaptic GABA B receptors in regulating kainate-induced subthreshold neuronal network oscillations in the gamma frequency range (25-80 Hz). The GABA B receptor agonist baclofen largely eliminated gamma oscillations. The GABA B receptor antagonist CGP55845 reversed this action of baclofen but alone did not alter the power or frequency of ongoing oscillations. To examine the role of synaptically released GABA on network activity, we electrically stimulated stratum radiatum of CA3 whilst recording gamma oscillations from stratum pyramidale. Single stimuli produced a pronounced transient (up to 1 s in duration) inhibition of gamma frequency oscillations. This stimulus-induced shutdown of network activity was enhanced by the GABA uptake inhibitor tiagabine and largely inhibited by CGP55845. Multiple stimuli delivered at frequencies of 1-3 Hz resulted in an activity-dependent fatigue of the inhibition of gamma activity, such that, after a number of stimuli, oscillations could be detected tens of milliseconds after the stimulus. Interestingly, this activity-dependent fatigue of inhibition uncovered a stimulus-dependent temporal entrainment of the gamma oscillations. Furthermore, the amount of repetitive synaptic input that was required to cause this entrainment was dramatically reduced by GABA B receptor antagonism such that it was evident within just a few stimuli. These data suggest that convergent afferent synaptic activity can alter the precise temporal arrangement of neuronal network activity. Furthermore, the flow of such information into a functioning neuronal network is highly regulated by GABA B receptor-mediated synaptic inhibition.

The suprachiasmatic nuclei (SCN) of the hypothalamus house the main circadian pacemaker in mammals. Vasoactive intestinal polypeptide (VIP) is the most abundant neuropeptide in the SCN and has been shown to phase-shift the electrical activity rhythm of SCN cells in vitro. However, the effects of VIP on the cellular activity of rat SCN neurones are unknown. In this study, we examined the acute effects of VIP on the extracellularly recorded spontaneous firing rate of SCN neurones in an in-vitro hypothalamic slice preparation. Furthermore, with the use of receptor-selective agonists and antagonists, we determined which receptors might mediate the effects of VIP in the SCN. Approximately 50% of cells responded to VIP; the main type of response was suppression in firing rate, although a few cells were activated. Suppression responses to VIP were mimicked by the VPAC(2) receptor agonist Ro 25-1553 and blocked by the selective VPAC(2) receptor antagonist PG 99-465. The PAC(1) receptor agonist maxadilan evoked responses from 40% of SCN cells, and activations to this agonist were not altered by PG 99-465. Responses to VIP were not blocked by antagonists to ionotropic glutamate receptors, but the duration of suppression was modulated by the GABA(A) receptor antagonist bicuculline. Our data indicate that VIP alters the electrical activity of rat SCN neurones in vitro, via both VPAC(2) and PAC(1) receptors.

analysis of the Tg2576 dentate gyrus proteome and transcriptome that is induced in response to cognitive-enhancing treatment with RSG that led us to discover that the PPARg and ERK/CREB/CBP signaling axes converge to enhance cognition. We found that these key integrators of cognitive performance in the Tg2576 model were central nodes within the GWAS LOAD loci network. Conclusions: These findings suggest the intriguing possibility that these GWAS LOAD loci may represent a functionally interrelated network with the PPARg and ERK/CREB/ CBP signaling axes. The molecular determinants of the convergence of these pathways may represent new targets for therapeutic intervention in cognitive enhancement in AD.