Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD). The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly correlated with cognitive impairment and amyloid-beta (Aβ) and tangle pathology. Hyperphosphorylated tau in the LC is among the first detectable AD-like neuropathology in the brain, and while the LC/NE system impacts multiple aspects of AD (e.g., cognition, neuropathology, and neuroinflammation), the functional consequences of hyperphosphorylated tau accrual on LC neurons are not known. Recent evidence suggests that LC neurons accumulate aberrant tau species for decades before frank LC cell body degeneration occurs in AD, suggesting that a therapeutic window exists. In this review, we combine the literature on how pathogenic tau affects forebrain neurons with the known properties and degeneration patterns of LC neurons to synthesize hypotheses on hyperphosphorylated tau-induced dysfunction of LC neurons and the prion-like spread of pretangle tau from the LC to the forebrain. We also propose novel experiments using both in vitro and in vivo models to address the many questions surrounding the impact of hyperphosphorylated tau on LC neurons in AD and its role in disease progression.
To investigate the mechanisms that maintain differentiated cells, here we inducibly delete the histone demethylase LSD1/KDM1A in adult mice. Loss of LSD1 leads to paralysis, along with widespread hippocampus and cortex neurodegeneration, and learning and memory defects. We focus on the hippocampus neuronal cell death, as well as the potential link between LSD1 and human neurodegenerative disease and find that loss of LSD1 induces transcription changes in common neurodegeneration pathways, along with the re-activation of stem cell genes, in the degenerating hippocampus. These data implicate LSD1 in the prevention of neurodegeneration via the inhibition of inappropriate transcription. Surprisingly, we also find that transcriptional changes in the hippocampus are similar to Alzheimer's disease (AD) and frontotemporal dementia (FTD) cases, and LSD1 is specifically mislocalized to pathological protein aggregates in these cases. These data raise the possibility that pathological aggregation could compromise the function of LSD1 in AD and FTD.
Recent studies show that the complex genetic architecture of schizophrenia (SZ) is driven in part by polygenic components, or the cumulative effect of variants of small effect in many genes, as well as rare single-locus variants with large effect sizes. Here we discuss genetic aberrations known as copy number variants (CNVs), which fall in the latter category and are associated with a high risk for SZ and other neuropsychiatric disorders. We briefly review recurrent CNVs associated with SZ, and then highlight one CNV in particular, a recurrent 1.6-Mb deletion on chromosome 3q29, which is estimated to confer a 40-fold increased risk for SZ. Additionally, we describe the use of genetic mouse models, behavioral tools, and patient-derived induced pluripotent stem cells as a means to study CNVs in the hope of gaining mechanistic insight into their respective disorders. Taken together, the genomic data connecting CNVs with a multitude of human neuropsychiatric disease, our current technical ability to model such chromosomal anomalies in mouse, and the existence of precise behavioral measures of endophenotypes argue that the time is ripe for systematic dissection of the genetic mechanisms underlying such disease.
Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G > T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.
We describe a novel preclinical model of stress-induced relapse to cocaine use in rats using social defeat stress, an ethologically valid psychosocial stressor in rodents that closely resembles stressors that promote craving and relapse in humans. Rats self-administered cocaine for 20 days. On days 11, 14, 17, and 20, animals were subjected to social defeat stress or a nonstressful control condition following the session, with discrete environmental stimuli signaling the impending event. After extinction training, reinstatement was assessed following re-exposure to these discrete cues. Animals re-exposed to psychosocial stress-predictive cues exhibited increased serum corticosterone and significantly greater reinstatement of cocaine seeking than the control group, and active coping behaviors during social defeat episodes were associated with subsequent reinstatement magnitude. These studies are the first to describe an operant model of psychosocial stress-induced relapse in rodents and lay the foundation for future work investigating its neurobiological underpinnings.
The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer's disease (AD). Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dose-dependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.
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Thea Hammerschmidt;
Markus P. Kummer;
Dick Terwel;
Ana Martinez;
Ali Gorji;
Hans-Christian Pape;
Karen Rommelfanger;
Jason Schroeder;
Monika Stoll;
Joachim Schultze;
David Weinshenker;
Michael T. Heneka
Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.
Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer?s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System.
Rationale: High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been propose d for the induction of seizures by cocaine, including enhanced monoaminergic signaling, blockade of ion channels, and alterations in GABA and glutamate transmission. Mutations in the SCN1A gene, which encodes the central nervous system (CNS) voltage-gated sodium channel (VGSC) Na v 1.1, are responsible for several human epilepsy disorders including Dravet syndrome and genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Mice heterozygous for the R1648H GEFS+ mutation (RH mice) exhibit reduced interneuron excitability, spontaneous seizures, and lower thresholds to flurothyl- and hyperthermia-induced seizures. However, it is unknown whether impaired CNS VGSC function or a genetic predisposition to epilepsy increases susceptibility to cocaine-induced seizures. Objectives: Our primary goal was to determine whether Scn1a dysfunction caused by the RH mutation alters sensitivity to cocaine-induced behavioral and electrographic (EEG) seizures. We also tested novelty- and cocaine-induced locomotor activity and assessed the expression of Na v 1.1 in midbrain dopaminergic neurons. Results: We found that RH mice had a profound increase in cocaine-induced behavioral seizure susceptibility compared to wild-type (WT) controls, which was confirmed with cortical EEG recordings. By contrast, although the RH mice were hyperactive in novel environments, cocaine-induced locomotor activity was comparable between the mutants and WT littermates. Finally, immunofluorescence experiments revealed a lack of Na v 1.1 immunoreactivity in dopaminergic neurons. Conclusion: These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.
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Joseph Cubells;
Jason Schroeder;
Elizabeth S. Barrie;
Daniel F. Manvich;
Wolfgang Sadee;
Tiina Berg;
Kristina Mercer;
Taylor A. Stowe;
L. Cameron Liles;
Katherine E. Squires;
Andrew Mezher;
Patrick Curtin;
Dannie L. Perdomo;
Patricia Szot;
David Weinshenker
Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice.