Cellular/Molecular
Serotonin Receptor Identifies Major Class of Cortical Interneuron
SooHyun Lee, Jens Hjerling-Leffler, Edward Zagha, Gord Fishell, Bernardo Rudy
(see pages 16796–16808)
GABAergic interneurons comprise ∼20% of cortical neurons in rodents and can be categorized by embryonic origin, protein expression profile, axonal arborization pattern, and electrophysiological properties. Despite ongoing taxonomic efforts, however, the number of functional classes of interneurons remains unknown. Approximately 70% of interneurons in mouse somatosensory cortex are generated in the medial ganglionic eminence and express either parvalbumin or somatostatin. Lee et al. report that the remaining ∼30% of interneurons express the ionotropic serotonin receptor (5-HT3aR) and nearly all originate in the caudal ganglionic eminence (CGE). In fact, all nine morphological and electrophysiological subtypes of CGE-derived interneurons express 5-HT3aR. Such interneurons are present in all cortical layers, but most reside in layers 1 and 2/3, where they are the predominant interneuron type. Regardless of subtype or layer, all 5-HT3aR-expressing interneurons are depolarized by 5-HT3aR agonist and by nicotine, which might provide state-dependent enhancement of monosynaptic thalamocortical inputs to these neurons.
A layer 5/6 5-HT3aR-expressing interneuron showing dendrites and soma (blue) and axon (red). See the article by Lee et al. for details.
Development/Plasticity/Repair
Intermittent Airway Obstruction Causes Long-Term Facilitation
Arash Tadjalli, James Duffin, and John Peever
(see pages 16886–16895)
Breathing involves rhythmic contraction of diaphragm and chest muscles, which creates negative pressure that causes lungs to inflate. The negative pressure can collapse upper airways, but this is normally prevented by coordinated rhythmic contraction of upper airway dilator muscles. During sleep, however, activity of airway dilators decreases, and this can allow pharyngeal collapse and temporary cessation of breathing (apnea). Obstructive sleep apnea (OSA) causes hypoxia, which in turn increases respiratory drive and causes arousal from sleep. Thus, OSA sufferers frequently awaken and are chronically sleepy. Tadjalli et al. describe a novel form of long-term facilitation (LTF) produced by intermittent airway obstruction that might be exploited to overcome OSA. This LTF required activation of α-adrenergic receptors on hypoglossal motor neurons, which innervate the largest airway dilator, and it increased muscle tone. Unlike previously described LTF, this LTF did not result from intermittent hypoxia, but was instead produced by intermittent disruption of vagal nerve activity.
Behavioral/Systems/Cognitive
AMPA Receptor Variation Is Linked to Stress Resilience
Mathias V. Schmidt, Dietrich Trümbach, Peter Weber, Klaus Wagner, Sebastian H. Scharf, et al.
(see pages 16949–16958)
Chronic stress during adolescence often contributes to later psychiatric illness, but some people are resilient to such stress. Resilience in humans has been linked to polymorphisms in several genes, including that encoding the serotonin transporter. Schmidt et al. report that variation in the AMPA receptor subunit GluR1 contributes to stress resilience in mice. Frequently changing cagemates of genetically diverse males increases corticosterone levels, but the rate at which levels decline varies across individuals. Mice exhibiting prolonged corticosterone elevation had lower hippocampal levels of GluR1 mRNA and higher levels of GluR2 mRNA than mice whose corticosterone levels dropped quickly. Interestingly, mice selectively bred for deficits in working memory also had increased levels of GluR2 mRNA, and they were more vulnerable to stress than mice bred for strong working memory. These differences were linked to a single-nucleotide polymorphism in the GluR1 gene. Mice with the stress-vulnerable variant were made stress-resilient by potentiating AMPA receptor function during stress exposure.
Neurobiology of Disease
Knock-out of LRP1 Causes Amyloid-Independent Synaptic Loss
Qiang Liu, Justin Trotter, Juan Zhang, Melinda M. Peters, Hua Cheng, et al.
(see pages 17068–17078)
Possession of the apolipoprotein E (apoE) ε4 allele is a major risk factor for late-onset Alzheimer's disease (AD). Why this isoform predisposes people to AD is unknown, but might be related to isoform differences in affinity for ApoE receptors, including the low-density-lipoprotein-receptor-related protein LRP1. ApoE delivers cholesterol and other lipids to neurons primarily via LRP1, but LRP1 also binds many other ligands. LRP1 interacts with amyloid precursor protein (APP), increasing its cleavage to form β-amyloid (Aβ), the chief component of AD plaques. LRP1 also aids in Aβ clearance. Altered ApoE–LRP1 interactions may affect these other functions. To explore its possible roles in AD, Liu et al. knocked out LRP1 in adult mouse forebrain neurons. This resulted in reduced brain levels of cholesterol and other lipids, loss of dendritic spines, reduced expression of glutamate receptor subunits, impaired memory, and neurodegeneration. Aβ levels were decreased in these mice, indicating that the other phenotypes were not a consequence of amyloidosis.
