Cellular/Molecular
The N-Terminal Portion of Aβ Enhances LTP
James L.M. Lawrence, Mei Tong, Naghum Alfulaij, Tessi Sherrin, Mark Contarino, et al.
(see pages 14210–14218)
Amyloid precursor protein (APP) is cleaved by three secretases, resulting in several peptide products. Sequential cleavage by β- then γ-secretases generates β-amyloid (Aβ) peptides of various lengths. Aβ activates nicotinic acetylcholine receptors (nAChRs) and at low concentrations it promotes long-term potentiation (LTP). But the aggregation-prone 42-amino-acid Aβ species, Aβ1–42, accumulates in Alzheimer's disease (AD), and high Aβ concentrations inhibit LTP. Normally, generation of Aβ1–42 is restrained by α-secretase, which cleaves APP in the middle of the Aβ sequence. Recent studies suggest that α-secretase can also cleave a β-secretase cleavage product of APP, yielding Aβ1–15. Lawrence et al. show that Aβ1–15 activates nAChRs at lower concentrations than Aβ1–42 and that low concentrations of Aβ1–15 also enhance LTP in mouse hippocampal slices. Unlike Aβ1–42, however, Aβ1–15 did not inhibit LTP at high concentrations; in fact, Aβ1–15 reversed impairment of LTP induced by high levels of Aβ1–42. Thus, stimulating α-secretase might have multiple benefits in AD.
Systems/Circuits
REM Transition Does Not Require Cholinergic Input to SubC
Kevin P. Grace, Lindsay E. Vanstone, and Richard L. Horner
(see pages 14198–14209)
Despite much investigation, the neural processes that initiate REM sleep remain uncertain. REM sleep requires activation of the subcoeruleus (SubC) region of the pons, and this activation has long been thought to depend on cholinergic input from pedunculopontine and laterodorsal tegemental nuclei (PPT and LDT, respectively). Indeed, cholinergic PPT and LDT neurons that innervate SubC are active during REM sleep, and administration of cholinergic agonists to SubC sometimes induces REM sleep. Nevertheless, inactivation of PPT and LDT does not reduce REM sleep and cholinergic agonists often induce prolonged wakefulness. Furthermore, Grace et al. report that microperfusion of muscarinic antagonists to rat SubC affected neither the frequency nor the total amount of REM sleep. The antagonist slightly reduced the duration of REM bouts, likely by prolonging the transition between non-REM and REM sleep, and it attenuated the increase in theta-frequency power that characterizes REM sleep. The authors propose that cholinergic input to SubC reinforces the non-REM-to-REM transition and contributes to the generation of theta oscillations.
Behavioral/Cognitive
Dopamine Enhances Cue-Evoked Excitation in Nucleus Accumbens
Johann du Hoffmann and Saleem M. Nicola
(see pages 14349–14364)
When reward-associated cues appear, dopamine is released in the nucleus accumbens (NAc), promoting approach toward anticipated rewards. Local interference with dopaminergic signaling selectively increases the latency to initiate approach behavior. Because both D1- and D2-type dopamine receptors (DRs) are expressed in NAc, and because some NAc neurons are excited while others are inhibited by reward-predicting cues, the cellular mechanism by which dopamine promotes approach is unresolved. To tackle this problem, du Hoffmann and Nicola used a probe that allowed localized delivery of DR antagonists to recorded NAc neurons. Presentation of reward-associated cues increased firing in ∼45% of recorded neurons. Bilateral infusion of either D1 or D2/D3 antagonist reduced cue-evoked excitation, and greater reductions were associated with greater latency to initiate approach behavior. Furthermore, neuronal and behavioral responses to cues recovered in parallel as the drugs wore off. In contrast, neither antagonist reduced inhibitory effects of reward-predicting cues. Thus, dopamine appears to stimulate approach by enhancing excitation of D1- and D2/3-expressing NAc neurons.
Presentation of a reward-predicting cue (at time indicated by vertical line) increased spiking of a neuron in NAc (red raster plot). Infusion of a D1DR antagonist reduced cue-induced spiking (blue raster plot). The presence of a behavioral response (indicated by horizontal lines to the left of rasters) depended on the size of the neuronal response. See the article by du Hoffmann and Nicola for details.
Neurobiology of Disease
Benefits of HDAC Inhibitors Extend beyond HDAC Inhibition
Sama F. Sleiman, David E. Olson, Megan W. Bourassa, Saravanan S. Karuppagounder, Yan-Ling Zhang, et al.
(see pages 14328–14337)
Epigenetic modifications such as histone acetylation and deacetylation underlie the long-term changes in transcriptional programs that occur during development, memory consolidation, and neurodegenerative diseases. Epigenetic modifiers are potential therapeutic targets; in fact, broad-spectrum histone deacetylase (HDAC) inhibitors are neuroprotective in animal models of multiple sclerosis and stroke. But identifying and targeting specific HDAC isoforms will be necessary to avoid substantial side effects of such therapies. Although progress has been made in this endeavor, Sleiman et al. raise a note of caution in interpreting studies in which the roles of specific HDACs is investigated solely through pharmacological means. They found that the neuroprotective effects of an isoform-selective HDAC8 inhibitor, PCI-34051, did not result from HDAC inhibition. PCI-34051 protected HDAC8-deficient mouse neurons from oxidative stress, and a methylated derivative of PCI-34051 that lacked HDAC-inhibitory action protected wild-type neurons. The neuroprotective effects of these molecules apparently depended on the presence of a metal-chelating hydroxamic acid moiety that is present in many HDAC inhibitors.
