Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

Homozygous or heterozygous mutations in the PTEN‐induced kinase 1 (PINK1) gene have been linked to early‐onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1‐deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate‐mediated synaptic events in the hippocampus, without influencing long‐term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. Synapse 70:223–230, 2016 . © 2016 Wiley Periodicals, Inc.     

BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment

Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain‐derived neurotrophic factor (BDNF) supports hippocampal long‐term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus‐dependent learning that occurs following EE. In the absence of EE, LTP elicited by high‐frequency stimulation was equivalent in wildtype mice and heterozygous BDNF^+/? siblings. LTP elicited by theta‐burst stimulation in BDNF^+/? mice was less than in wildtypes. Long‐term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF^+/? mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Late onset sporadic Parkinson's disease caused by PINK1 mutations: Clinical and functional study

Homozygous or compound heterozygous mutations in the PINK1 gene represent the second most frequent cause of autosomal recessive parkinsonism after Parkin. The phenotype differs from idiopathic Parkinson's disease for earlier onset, slower disease progression, and better response to therapy. Indeed, the rare patients with onset above 50 years are usually relatives of early‐onset probands. Here, we report the first occurrence of compound heterozygous PINK1 mutations in a sporadic patient with a phenotype indistinguishable from idiopathic Parkinson's disease (PD), with onset in the late seventh decade, rapid progression and good response to levodopa that waned with time. Both mutations (p.A244G and p.V317I) were found to abolish the protective effect of wild‐type PINK1 against staurosporine‐induced apoptosis. These findings further expand the clinical spectrum of PINK1‐related parkinsonism to include late onset, typical PD, and underline the existing difficulties in discriminating between mendelian parkinsonism and idiopathic PD. © 2008 Movement Disorder Society     

Impaired dopaminergic neuron development and locomotor function in zebrafish with loss of pink1 function

Mutations in the human PTEN‐induced kinase 1 (PINK1) gene are linked to recessive familial Parkinson’s disease. Animal models of altered PINK1 function vary greatly in their phenotypic characteristics. Drosophila pink1 mutants exhibit mild dopaminergic neuron degeneration and locomotion defects. Such defects are not observed in mice with targeted null mutations in pink1, although these mice exhibit impaired dopamine release and synaptic plasticity. Here, we report that in zebrafish, morpholino‐mediated knockdown of pink1 function did not cause large alterations in the number of dopaminergic neurons in the ventral diencephalon. However, the patterning of these neurons and their projections are perturbed. This is accompanied by locomotor dysfunction, notably impaired response to tactile stimuli and reduced swimming behaviour. All these defects can be rescued by expression of an exogenous pink1 that is not a target of the morpholinos used. These results indicate that normal PINK1 function during development is necessary for the proper positioning of populations of dopaminergic neurons and for the establishment of neuronal circuits in which they are implicated.     

Disruption of hippocampus‐regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP

The brain‐specific Ras/Rap‐GTPase activating protein (SynGAP) is a prime candidate linking N‐methyl‐d ‐aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience‐dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG^+/?), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG^+/? mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T‐maze. In the non‐cognitive domain, SG^+/? mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG^+/? mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non‐cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin‐positive interneurons in the hippocampus and doublecortin‐positive neurons in the dentate gyrus of adult SG^+/? mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.     

Olfactory dysfunction in Parkinsonism caused by PINK1 mutations

Hyposmia is a common nonmotor feature of Parkinson's disease (PD) and has been variably detected in monogenic Parkinsonisms. To assess olfactory dysfunction in PINK1‐related Parkinsonism, we evaluated olfactory detection threshold, odor discrimination, and odor identification in five groups of subjects: sporadic PD (n = 19), PINK1 homozygous (n = 7), and heterozygous (n = 6) parkinsonian patients, asymptomatic PINK1 heterozygous carriers (n = 12), and Italian healthy subjects (n = 67). All affected subjects and all healthy heterozygotes but one resulted hyposmic, with most patients in the range of functional anosmia or severe hyposmia. Detection threshold was more preserved and discrimination more impaired in patients with PINK1 mutations than in PD cases. Alterations of detection and discrimination were observed also in PINK1 asymptomatic heterozygotes. On the contrary, odor identification appeared to be mostly related to the disease status, as it was impaired in nearly all patients (including PD and PINK1 cases) and preserved in healthy heterozygotes. Our data indicate that olfactory dysfunction is common in PINK1 Parkinsonism and consists typically in defective odor identification and discrimination. A milder olfactory deficit, mostly involving discrimination, can be found in asymptomatic heterozygotes, possibly indicating an underlying preclinical neurodegenerative process. © 2009 Movement Disorder Society     

PINK1 mutation in Taiwanese early-onset parkinsonism

Abstract The PINK1 gene mutation is probably the second most common genetic cause of early-onset Parkinson's disease (EOPD). The frequency and the characteristics of the PINK1 mutation in the Taiwanese population are unknown. This study was designed to investigate the genotype, phenotype and dopaminergic function of PINK1 in a cohort of EOPD patients. The genetic settings were to detect the PINK1 gene mutations in 138 EOPD patients and in 191 controls. Using the ^99mTc-TRODAT-1 (TRODAT) scan, we investigated the differences in the dopamine transporter (DAT) activities between the PINK1 patients, late-onset Parkinson's disease (LOPD) patients and healthy controls. Four EOPD patients with 3 genotypic mutations in the PINK1 gene were found: a compound heterozygous mutation (Q239X/R492X) in 2 sisters, a novel homozygous mutation (R492X) in a woman, and a novel heterozygous mutation (G193R) in a man. The three PINK1 patients had typical phenotype with juvenile onset, benign course, and frequently with dyskinesias. The TRODAT scan showed a rather even and symmetrical reduction of uptake in PINK1 patients, unlike the dominant decline in the putamen in the LOPD patients. The annual reduction rate of uptake in the striatum was much slower in PINK1 patients than that in the LOPD patients (1.7 % vs. 4.1%; p<0.005). In the patient with a heterozygous mutation in the PINK1 gene, the reduction ratio in the striatum, as well as the annual reduction rate, were closer to those in the LOPD group. We conclude that the incidence of carrying PINK1 mutations in the present cohort of Taiwanese EOPD patients was low, accounting for 2/39 (5.1 %) in familial cases, and 2/99 (2 %) in sporadic cases. The slower annual reduction of DAT activity might indicate the insidious degeneration of dopamine neurons and a benign prognosis.     

Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease

Early onset Parkinson's disease (EOPD) has been associated with mutations in the Parkin, DJ‐1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset ≤ 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ‐1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ‐1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ‐1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution. © 2008 Movement Disorder Society     

Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin

An altered glutamatergic input at corticostriatal synapses has been shown in experimental models of Parkinson's disease (PD). In the present work, we analyzed the membrane and synaptic responses of striatal neurons to metabotropic glutamate (mGlu) receptor activation in two different mouse models of inherited PD, linked to mutations in PINK1 or Parkin genes.Both in PINK1 and Parkin knockout (^−/−) mice, activation of group I mGlu receptors by 3,5-DHPG caused a membrane depolarization coupled to an increase in firing frequency in striatal cholinergic interneurons that was comparable to the response observed in the respective wild-type (WT) interneurons. The sensitivity to group II and III mGlu receptors was tested on cortically-evoked excitatory postsynaptic potentials (EPSPs) recorded from medium spiny neurons (MSNs). Both LY379268 and L-AP4, agonists for group II and III, respectively, had no effect on intrinsic membrane properties, but dose-dependently reduced the amplitude of corticostriatal EPSPs. However, both in PINK1^−/− and Parkin^−/− mice, LY379268, but not L-AP4, exhibited a greater potency as compared to WT in depressing EPSP amplitude. Accordingly, the dose–response curve for the response to LY379268 in both knockout mice was shifted leftward. Moreover, consistent with a presynaptic site of action, both LY379268 and L-AP4 increased the paired-pulse ratio either in PINK1^−/− and Parkin^−/− or in WT mice. Acute pretreatment with L-dopa did not rescue the enhanced sensitivity to LY379268.Together, these results suggest that the selective increase in sensitivity of striatal group II mGlu receptors represents an adaptive change in mice in which an altered dopamine metabolism has been documented.     

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors

Broad‐spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short‐ and long‐term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock‐in (Tor1a^+/Δgag) mice heterozygous for ΔE‐torsinA and their controls (Tor1a^+/+ mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M₁ antagonist, VU0255035. Tor1a^+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short‐term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long‐term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M₁‐preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M₁ receptors was further demonstrated by their ability to counteract the M₁‐dependent potentiation of N‐methyl‐d ‐aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M₁ muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. © 2014 International Parkinson and Movement Disorder Society     

Enhanced cognition and dysregulated hippocampal synaptic physiology in mice with a heterozygous deletion of PSD‐95

PSD‐95 is one of the most abundant proteins of the postsynaptic density of excitatory synapses. It functions as the backbone of protein supercomplexes that mediate signalling between membrane glutamate receptors and intracellular pathways. Homozygous deletion of the Dlg4 gene encoding PSD‐95 was previously found to cause a profound impairment in operant and Pavlovian conditioning in Dlg4^?/? mice studied in touch screen chambers that precluded evaluation of PSD‐95's role in shaping more subtle forms of learning and memory. In this study, using a battery of touch screen tests, we investigated cognitive behaviour of mice with a heterozygous Dlg4 mutation. We found that in contrast to learning deficits of Dlg4^?/? mice, Dlg4^+/? animals demonstrated enhanced performance in the Visual Discrimination, Visual Discrimination Reversal and Paired‐Associates Learning touch screen tasks. The divergent directions of learning phenotypes observed in Dlg4^?/? and Dlg4^+/? mice also contrasted with qualitatively similar changes in the amplitude and plasticity of field excitatory postsynaptic potentials recorded in the CA1 area of hippocampal slices from both mutants. Our results have important repercussions for the studies of genetic models of human diseases, because they demonstrate that reliance on phenotypes observed solely in homozygous mice may obscure qualitatively different changes in heterozygous animals and potentially weaken the validity of translational comparisons with symptoms seen in heterozygous human carriers.     

Deficiency of ganglioside GM1 correlates with Parkinson's disease in mice and humans

Several studies have successfully employed GM1 ganglioside to treat animal models of Parkinson's disease (PD), suggesting involvement of this ganglioside in PD etiology. We recently demonstrated that genetically engineered mice (B4galnt1^?/?) devoid of GM1 acquire characteristic symptoms of this disorder, including motor impairment, depletion of striatal dopamine, selective loss of tyrosine hydroxylase‐expressing neurons, and aggregation of α‐synuclein. The present study demonstrates similar symptoms in heterozygous mice (HTs) that express only partial GM1 deficiency. Symptoms were alleviated by administration of L‐dopa or LIGA‐20, a membrane‐permeable analog of GM1 that penetrates the blood–brain barrier and accesses intracellular compartments. Immunohistochemical analysis of paraffin sections from PD patients revealed significant GM1 deficiency in nigral dopaminergic neurons compared with age‐matched controls. This was comparable to the GM1 deficiency of HT mice and suggests that GM1 deficiency may be a contributing factor to idiopathic PD. We propose that HT mice with partial GM1 deficiency constitute an especially useful model for PD, reflecting the actual pathophysiology of this disorder. The results point to membrane‐permeable analogs of GM1 as holding promise as a form of GM1 replacement therapy. © 2012 Wiley Periodicals, Inc.     

PINK1 mutations in a Brazilian cohort of early‐onset Parkinson's disease patients

Data on the frequency of PINK1 mutations in Brazilian patients with early‐onset Parkinson's disease (EOPD) are lacking. The aim of this report was to investigate mutations of the PINK1 gene in a cohort of Brazilian patients with EOPD. Sixty consecutive familial or sporadic EOPD patients were included. All eight PINK1 exons and exon‐intron boundaries were analyzed. We did not find any pathogenic mutation of PINK1 in our cohort. Single Nucleotide Polymorphisms (SNP) were identified in 46.7% of the patients and in 45.9% of controls (P = 0.9). The SNPs identified in our patients had already been described in previous reports. The results of our study support the hypothesis that mutations in PINK1 may not be a relevant cause of EOPD. In Brazil, if we consider only EOPD patients, it seems that parkin and LRRK2 mutations are more common. © 2009 Movement Disorder Society     

PINK1 mutation heterozygosity and the risk of Parkinson's disease

Background

Mutations in the PTEN‐induced kinase 1 (PINK1) gene have been identified in recessively inherited and sporadic early‐onset parkinsonism (EOP).

Methods

A total of 131 Norwegian patients diagnosed with Parkinson''s disease were included. Of them, 89 participants had EOP (onset ⩽50 years); the remaining had familial late‐onset disease (mean age at onset 64 years). PINK1 analysis included sequencing and gene dose assessment. Mutations were examined in 350 controls .

Results

Heterozygous missense mutations in PINK1 were found in 3 of 131 patients; none of the patients carried homozygous or compound heterozygous mutations. One of these three patients had a father affected by Parkinson''s disease, and he carried the mutation. Three new and seven known polymorphic variants were identified, although none seemed to be associated with disease risk.

Conclusions

PINK1 mutations are rare in Norwegian patients with EOP and familial Parkinson''s disease. However, the data suggest that some heterozygous mutations might increase the risk of developing Parkinson''s disease.The causes of Parkinson''s disease are still largely unknown. Evidence suggests that both environmental factors and genetic susceptibility contribute to disease aetiology.¹ Familial parkinsonism can be inherited as an autosomal dominant or recessive trait. Mutations in three genes have been associated with recessively inherited early‐onset parkinsonism (EOP): parkin, DJ‐1 and PTEN‐induced kinase 1 (PINK1). Mutations in the parkin gene may account for nearly 50% of familial and a considerable proportion of apparently sporadic EOP (with age of onset ⩽45 years).² Pathogenic mutations in the DJ‐1 gene seem to be rare, causing <1% of EOP cases.³Missense mutations in the PINK1 gene were first identified in three consanguineous Italian and Spanish kindreds affected with EOP.⁴ Mutations in this gene have now been found in families originating from several European and Asian populations, making PINK1 the second most common genetic known cause of EOP.^5,6,7,8,9PINK1 mutations have also been identified in patients with sporadic disease, including heterozygous mutations of unknown pathogenicity.^10,11 To further evaluate the pathogenic role of PINK1 mutations in familial and sporadic Parkinson''s disease, we performed a comprehensive mutation analysis of this gene in a series of Norwegian patients with Parkinson''s disease.     

Parkin promotes proteasomal degradation of synaptotagmin IV by accelerating polyubiquitination

Parkin is an E3 ubiquitin ligase whose mutations cause autosomal recessive juvenile Parkinson's disease (PD). Unlike the human phenotype, parkin knockout (KO) mice show no apparent dopamine neuron degeneration, although they demonstrate reduced expression and activity of striatal mitochondrial proteins believed to be necessary for neuronal survival. Instead, parkin-KO mice show reduced striatal evoked dopamine release, abnormal synaptic plasticity, and non-motor symptoms, all of which appear to mimic the preclinical features of Parkinson's disease. Extensive studies have screened candidate synaptic proteins responsible for reduced evoked dopamine release, and synaptotagmin XI (Syt XI), an isoform of Syt family regulating membrane trafficking, has been identified as a substrate of parkin in humans. However, its expression level is unaltered in the striatum of parkin-KO mice. Thus, the target(s) of parkin and the molecular mechanisms underlying the impaired dopamine release in parkin-KO mice remain unknown. In this study, we focused on Syt IV because of its highly homology to Syt XI, and because they share an evolutionarily conserved lack of Ca^2 +-binding capacity; thus, Syt IV plays an inhibitory role in Ca^2 +-dependent neurotransmitter release in PC12 cells and neurons in various brain regions. We found that a proteasome inhibitor increased Syt IV protein, but not Syt XI protein, in neuron-like, differentiated PC12 cells, and that parkin interacted with and polyubiquitinated Syt IV, thereby accelerating its protein turnover. Parkin overexpression selectively degraded Syt IV protein, but not Syt I protein (indispensable for Ca^2 +-dependent exocytosis), thus enhancing depolarization-dependent exocytosis. Furthermore, in parkin-KO mice, the level of striatal Syt IV protein was increased. Our data indicate a crucial role for parkin in the proteasomal degradation of Syt IV, and provide a potential mechanism of parkin-regulated, evoked neurotransmitter release.     

Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

Basal ganglia disorders such as Parkinson's disease, dystonia, and Huntington's disease are characterized by a dysregulation of the basal ganglia neuromodulators (dopamine, acetylcholine, and others), which impacts cortico‐striatal transmission. Basal ganglia disorders are often associated with an imbalance between the midbrain dopaminergic and striatal cholinergic systems. In contrast to the extensive research and literature on the consequences of a malfunction of midbrain dopaminergic signaling on the plasticity of the cortico‐striatal synapse, very little is known about the role of striatal cholinergic interneurons in normal and pathological control of cortico‐striatal transmission. In this review, we address the functional role of striatal cholinergic interneurons, also known as tonically active neurons and attempt to understand how the alteration of their functional properties in basal ganglia disorders leads to abnormal cortico‐striatal synaptic plasticity. Specifically, we suggest that striatal cholinergic interneurons provide a permissive signal, which enables long‐term changes in the efficacy of the cortico‐striatal synapse. We further discuss how modifications in the striatal cholinergic activity pattern alter or prohibit plastic changes of the cortico‐striatal synapse. Long‐term cortico‐striatal synaptic plasticity is the cellular substrate of procedural learning and adaptive control behavior. Hence, abnormal changes in this plasticity may underlie the inability of patients with basal ganglia disorders to adjust their behavior to situational demands. Normalization of the cholinergic modulation of cortico‐striatal synaptic plasticity may be considered as a critical feature in future treatments of basal ganglia disorders. © 2015 International Parkinson and Movement Disorder Society     

Systematic Review and UK‐Based Study of PARK2 (parkin), PINK1, PARK7 (DJ‐1) and LRRK2 in early‐onset Parkinson's disease

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early‐onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late‐onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high‐ascertainment regional and community‐based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ‐1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first‐degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ‐1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity. © 2012 Movement Disorder Society.     

123I‐Ioflupane SPECT in the diagnosis of suspected psychogenic Parkinsonism

Psychogenic Parkinsonism (PsyP) can be clinically difficult to differentiate from Parkinson's disease (PD). Striatal dopamine transporter (DAT) imaging could be helpful in differentiating them. We performed ¹²³I‐Ioflupane single‐photon emission computed tomography (SPECT) in 9 patients with suspected PsyP. In 1 patient, ¹²³I‐Ioflupane SPECT disclosed bilateral decrease of striatal tracer uptake that indicated nigrostriatal degeneration. In this patient, a parkin gene mutation was detected. In the other 8 patients, ¹²³I‐Ioflupane SPECT was normal and supported the initial suspicion of PsyP. Normal DAT imaging supports the diagnosis of PsyP, whereas reduced striatal tracer uptake suggests an underlying neurodegenerative Parkinsonism and should encourage the search for additional causes for the syndrome. © 2006 Movement Disorder Society     

Syntaxin 1B contributes to regulation of the dopaminergic system through GABA transmission in the CNS

In neuronal plasma membrane, two syntaxin isoforms, HPC‐1/syntaxin 1A (STX1A) and syntaxin 1B (STX1B), are predominantly expressed as soluble N‐ethylmaleimide‐sensitive fusion attachment protein receptors, also known as t‐SNAREs. We previously reported that glutamatergic and GABAergic synaptic transmissions are impaired in Stx1b null mutant (Stx1b^?/?) mice but are almost normal in Stx1a null mutant (Stx1a^?/?) mice. These observations suggested that STX1A and STX1B have distinct functions in fast synaptic transmission in the central nervous system (CNS). Interestingly, recent studies indicated that Stx1a^?/? or Stx1a^+/? mice exhibit disruption in the monoaminergic system in the CNS, causing unusual behaviour that is similar to neuropsychological alterations observed in psychiatric patients. Here, we studied whether STX1B contributes to the regulation of monoaminergic system and if STX1B is related to neuropsychological properties in human neuropsychological disorders similar to STX1A. We found that monoamine release in vitro was normal in Stx1b^+/? mice unlike Stx1a^?/? or Stx1a^+/? mice, but the basal extracellular dopamine (DA) concentration in the ventral striatum was increased. DA secretion in the ventral striatum is regulated by GABAergic neurons, and Stx1b^+/? mice exhibited reduced GABA release both in vitro and in vivo, disrupting the DAergic system in the CNS of these mice. We also found that Stx1b^+/? mice exhibited reduced pre‐pulse inhibition (PPI), which is believed to represent one of the prominent schizotypal behavioural profiles of human psychiatric patients. The reduction in PPI was rescued by DA receptor antagonists. These observations indicated that STX1B contributes to excess activity of the DAergic system through regulation of GABAergic transmission.