Madaline B. Harrison

Selective localization of striatal D1 receptors to striatonigral neurons.

A new technique for producing anatomically selective lesions within the brain was used to investigate the cellular localization of the D1 and D2 receptor. The cytotoxic lectin, volkensin, is taken up by nerve terminals and retrogradely transported, killing those neurons projecting to the site of injection. Comparison of D1 and D2 binding following a unilateral volkensin injection into the substantia nigra has demonstrated that striatal D1 binding sites are selectively localized to striatonigral projection neurons.

Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study

BackgroundAge at onset of Huntingtons disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.MethodsIn order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.ResultsSuggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.ConclusionIn this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Changes in D2 but not D1 receptor binding in the striatum following a selective lesion of striatopallidal neurons

We have used the immunotoxin OX7/saporin, a suicide transport agent, to selectively lesion striatopallidal neurons. Following injection of OX7/saporin into the globus pallidus, in situ hybridization for preproenkephalin mRNA was examined in the striatum to confirm successful retrograde neurotoxicity. Comparison of D1 and D2 receptor binding in the striatum demonstrated that D2 but not D1 receptor binding sites are localized to striatopallidal neurons.

Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Abstract.Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Δ2642 (within the HD coding sequence), and BJ56 (D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Δ2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

Differential localization of A2a adenosine receptor mRNA with D1 and D2 dopamine receptor mRNA in striatal output pathways following a selective lesion of striatonigral neurons

We have used the suicide transport agent volkensin to produce selective lesions of striatonigral neurons. By in situ hybridization histochemistry unilateral volkensin injections in the substantia nigra decreased the number of D1 receptor mRNA-expressing neurons in the ipsilateral striatum but did not change the number of D2 receptor and A2a adenosine receptor mRNA-expressing neurons. These findings confirm that striatonigral neurons express D1 receptors and suggest that D2-A2a receptor expressing neurons are predominantly localized to other neuronal populations within the striatum.

UPDRS activity of daily living score as a marker of Parkinson's disease progression

The activities of daily living (ADL) subscore of the Unified Parkinsons Disease Rating Scale (UPDRS) captures the impact of Parkinsons disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross‐sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

Synaptic and Extrasynaptic Localization of Brain-Derived Neurotrophic Factor and the Tyrosine Kinase B Receptor in Cultured Hippocampal Neurons

Brain‐derived neurotrophic factor (BDNF) regulates synapses, but the distribution of BDNF and its receptor TrkB relative to the location of glutamatergic and γ‐aminobutyric acidergic (GABAergic) synapses is presently unknown. Immunocytochemistry was performed in primary hippocampal neuron cultures to determine whether BDNF and TrkB are preferentially localized to excitatory or inhibitory markers at 7, 14, and 21 days in vitro (DIV). Glutamatergic sites were localized with vesicular glutamate transporter type 1 (VGLUT1) as presynaptic marker and the NR1 subunit of the NMDA receptor and the GluR1 subunit of the AMPA receptor as receptor markers. GABAergic sites were labeled with the 65‐kDa isoform of glutamic acid decarboxylase (GAD‐65) as presynaptic marker and the γ2 subunit of the GABAA receptor as receptor marker. During development, <30% of BDNF punctae and TrkB clusters were localized to glutamatergic and GABAergic markers. Because their rates of colocalization did not change from 7 to 21 DIV, this study details the distribution of BDNF and TrkB at 14 DIV. BDNF was preferentially colocalized with glutamatergic markers VGLUT1 and NR1 (∼30% each). TrkB was also relatively highly colocalized with VGLUT1 and NR1 (∼20% each) but was additionally highly colocalized with GABAergic markers GAD‐65 (∼20%) and γ2 (∼30%). NR1 clusters colocalized with BDNF puncta and TrkB clusters were mostly extrasynaptic, as were γ2 clusters colocalized with TrkB clusters. These results show that, whereas most BDNF and TrkB protein is extrasynaptic, BDNF is preferentially associated with excitatory markers and that TrkB is associated equally with excitatory and inhibitory markers. J. Comp. Neurol. 478:405–417, 2004.

Gender ratio differences between Parkinson's disease patients and their affected relatives

Mitochondrial dysfunction in Parkinsons disease (PD) is suspected to arise from either acquired or inherited mutation of mitochondrial DNA (mtDNA). If inherited, epidemiologic analysis may reveal maternal transmission. We looked for maternal inheritance bias in our PD clinical database. About 13% of 600 PD probands reported an affected parent. Although 60% of the PD probands were male, only 42% of the affected parents were. The gender ratios for the proband and affected parent generations were dissimilar (p<0.005), indicating an underrepresentation of affected fathers or an overrepresentation of affected mothers. To address these possibilities we analyzed a non-PD control cohort. Four percent of the controls had a PD affected parent, and 75% of these affected parents were male. Apparent maternal inheritance bias in our PD cohort is therefore more likely due to overrepresentation of affected mothers, and is consistent with mitochondrial inheritance in some of our ascertained cases.

Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy.

Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication‐refractory essential tremor. Recently, the development of transcranial, high‐intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire.

Expression of m1 and m4 muscarinic receptor mRNA in the striatum following a selective lesion of striatonigral neurons

Cholinergic stimulation has opposing effects on striatopallidal and striatonigral neurons. Most striatal projection neurons express m1 muscarinic receptor mRNA with m4 mRNA found in 40-50%. Expression of m4 mRNA is found in most preprotachykinin neurons but only a subset of preproenkephalin neurons, suggesting preferential localization of m4 receptors to striatonigral neurons. A volkensin lesion of striatonigral neurons reduced striatal m4 mRNA by 63% and m1 mRNA by only 18%, suggesting that preferential expression of m4 receptors by striatonigral neurons may contribute to their differential response.