The alpha7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is abundantly expressed in hippocampus and is implicated in modulating neurotransmitter release and in binding alpha-bungarotoxin (alpha-BGT). A null mutation for the alpha7 subunit was prepared by deleting the last three exons of the gene. Mice homozygous for the null mutation lack detectable mRNA, but the mice are viable and anatomically normal. Neuropathological examination of the brain revealed normal structure and cell layering, including normal cortical barrel fields; histochemical assessment of the hippocampus was also normal. Autoradiography with [3H]nicotine revealed no detectable abnormalities of high-affinity nicotine binding sites, but there was an absence of high-affinity [125I]alpha-BGT sites. Null mice also lack rapidly desensitizing, methyllycaconitine-sensitive, nicotinic currents that are present in hippocampal neurons. The results of this study indicate that the alpha-BGT binding sites are equivalent to the alpha7-containing nAChRs that mediate fast, desensitizing nicotinic currents in the hippocampus. These mice demonstrate that the alpha7 subunit is not essential for normal development or for apparently normal neurological function, but the mice may prove to have subtle phenotypic abnormalities and will be valuable in defining the functional role of this gene product in vivo.

Transcripts for the beta2 and the beta4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two beta subunits can form heteromultimeric channels with any of the alpha2, alpha3, alpha4, or alpha5 subunits in heterologous expression systems. Nonetheless, the subunit composition of native nAChRs and the role of different nAChR subtypes in vivo remain unclear. We prepared null mutations for the beta2 and the beta4 genes and bred beta2-/-beta4-/- mice by mating mice of identical beta2-/-beta4+/- or beta2+/-beta4-/- genotype. The beta2-/- and the beta4-/- single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The beta2-/-beta4-/- double mutants survive to birth but have impaired growth and increased perinatal mortality. They also present enlarged bladders with dribbling urination and develop urinary infection and bladder stones. The ocular pupils are widely dilated and do not constrict in response to light. Histological studies revealed no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta4-/- and beta2-/-beta4-/- mutants. Bladder strips from beta2-/-beta4-/- mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from beta4 mutants did not respond to nicotine despite the absence of major bladder dysfunction in vivo. Acetylcholine-activated whole-cell currents were absent in superior cervical ganglion neurons from beta2-/-beta4-/- mice and reduced in neurons from beta4-/- mice. Although there is apparent redundancy and a superficially normal phenotype in beta2-/- and beta4-/- mice, physiological studies indicate major deficits in the beta4-/- mice. Our previous description of a similar phenotype in alpha3-/- mice and the current data suggest that the alpha3 and the beta4 subunits are major components in autonomic nAChRs. The phenotype of the beta2-/-beta4-/- and alpha3-/- mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.

Background-The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson's disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson's disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson's disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson's disease.

Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. Results:The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by nigrostriatal dopamine depletion. The motor symptoms of PD appear only when dopaminergic cell death reaches a critical threshold of 50% to 80%.1 This suggests that the nervous system has a marked potential to compensate for these changes.2 However, human studies of cerebral compensation in premotor PD are lacking, given the difficulty of predicting who will develop PD in the future.Previous work has shown that compensatory mechanisms in idiopathic PD depend on brain regions relatively unaffected by dopamine depletion, such as the anterior striatum.3,4 Using fMRI in early-stage PD, we recently showed a shift in corticostriatal connectivity from severely affected striatal regions (posterior putamen) to less affected striatal regions (anterior putamen). 5If these changes reflect compensation, they should also occur in the premotor phase of PD, when functional reorganization of cerebral circuits prevents overt clinical symptoms. 2 *These authors contributed equally to this work.

Abstract:The ␣7 nicotinic acetylcholine receptor (nAChR) has been implicated in modulating neurotransmitter release and may play a role in the regulation of neuronal growth and differentiation. A threonine for leucine 247 substitution in the channel domain of the chick ␣7 nAChR increases agonist affinity and decreases the rate of desensitization, creating a "gain of function" model for this receptor. We have generated mice that express the analogous mutation (L250T) in the ␣7 nAChR using the techniques of homologous recombination and here report their characteristics. Mice heterozygous (ϩ/ T ) for the L250T mutation are viable, fertile, and anatomically normal compared with wild-type littermates. In contrast, homozygous (T/ T ) L250T mice die within 2-24 h of birth. Brains of T/ T mouse pups exhibit a marked reduction in ␣7 nAChR protein levels and show extensive apoptotic cell death throughout the somatosensory cortex. Furthermore, ␣7 L250T nAChRs are functionally expressed on neurons within the brains of T/ T neonatal mice and have properties that are consistent with those observed for the rat ␣7 L250T and the chick ␣7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing only ␣7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possibly due to increased Ca 2ϩ influx. Key Words: ␣-Bungarotoxin-Nicotine-AcetylcholineCholinergic-Somatosensory cortex-Apoptosis. J. Neurochem. 74, 2154 -2166 (2000).Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the vertebrate PNS and CNS. Eleven genes encoding neuronal nAChR subunits have been identified and designated ␣2-␣9 and ␤2-␤4 Changeux et al., 1998). Despite their diversity in subunit composition, pharmacology, and function (Albuquerque et al., 1997), neuronal nAChRs fall into two classes, based on their sensitivity to the snake toxin ␣-bungarotoxin (␣-BTX). Moreover, these two classes of nAChRs show distinct distribution patterns in the CNS (Clarke et al., 1985).In the mammalian brain, ␣-BTX-sensitive nAChRs are known to contain ␣7 subunits, which can form homooligomeric ion channels (Chen and Patrick, 1997; OrrUrtreger et al., 1997). Both native and recombinant ␣7-containing nAChRs are highly permeable to Ca 2ϩ and are blocked by nanomolar concentrations of ␣-BTX (Seguela et al., 1993;Castro and Albuquerque, 1995). Furthermore, activation of ␣7 nAChRs can produce a rapidly decaying inward current that can quickly elevate intracellular Ca 2ϩ levels in neurons (Vijayaraghavan et al., 1992;Zhang et al., 1994).Increasing evidence suggests that ␣7 nAChRs found at presynaptic terminals throughout the CNS play a role in modulating the release of several neurotransmitters Alkondon et al., 1996;Gray et al., 1996;Liang and Vizi, 1997;Aramakis and Metherate, 1998;Li et al., 1998;Zarei et al., 1999) through a Ca 2ϩ -dependent mechanism. Recent studies have also demonstrated evoked synaptic currents in hippocampal interneurons, mediated by post-and extrasynaptic ␣7 ...

BackgroundSleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum.ObjectivesWe assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication.MethodsA total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri‐axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright ‐time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements.ResultsNocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication.ConclusionsUsing wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society

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