Nuclear and neuritic distribution of serine-129 phosphorylated α-synuclein in transgenic mice

Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the α-synuclein (αSYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of αSYN protein fibrils. Moreover, αSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]αSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)–[A30P]αSYN transgenic mice further developed age-dependent, specific neuritic/terminal αSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-[A30P]αSYN mice. Thus, αSYN becomes phosphorylated in distinct parts of the brain in this α-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.     

Selective Insolubility of α-Synuclein in Human Lewy Body Diseases Is Recapitulated in a Transgenic Mouse Model

alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.     

Ibuprofen ameliorates protein aggregation and astrocytic gliosis, but not cognitive dysfunction, in a transgenic mouse expressing dementia with Lewy bodies-linked P123H β-synuclein

Epidemiological studies have shown that ibuprofen, a non-steroidal anti-inflammatory drug, reduces the risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this context, it has been shown that chronic treatment with ibuprofen improves cognitive dysfunction and histopathologic outcome in mouse models of AD. However, the therapeutic effects of ibuprofen in animal models of PD and related synucleinopathies such as dementia with Lewy bodies (DLB) have not been investigated. Therefore, the main objective of this study was to determine if ibuprofen ameliorates neuropathology and cognitive dysfunction in a transgenic (tg) mouse expressing DLB-linked P123H β-synuclein. P123H β-synuclein tg mice and their non-tg littermates aged 3 months were given ibuprofen in their diet (n=13). Controls did not receive ibuprofen (n=11). After 3 months, the mice were evaluated using a Morris water maze test, followed by neuropathological analyses. Compared to control P123H β-synuclein tg mice, P123H β-synuclein tg mice that received ibuprofen had significantly reduced protein aggregation and astrogliosis. However, ibuprofen treatment produced little improvement of the learning disability of P123H β-synuclein tg mice in the Morris water maze test. These results suggest that amelioration of neuropathologies by ibuprofen does not necessarily lead to improved cognitive function in synucleinopathies such as DLB.     

Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies

alpha-Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders in which abnormal inclusions containing alpha-synuclein accumulate in selectively vulnerable neurons and glia. In this report, immunohistochemistry demonstrates ubiquitin in subsets of alpha-synuclein inclusions in dementia with Lewy bodies and multiple system atrophy. Biochemistry demonstrates that alpha-synuclein in the sodium dodecyl sulfate-soluble fractions of diseased brains is ubiquitinated, with mono- and di-ubiquitinated species predominating over polyubiquitinated forms. Similar immunohistochemical and biochemical characteristics were observed in an A53T mutant human alpha-synuclein transgenic mouse model of neurodegenerative alpha-synucleinopathies. Furthermore, in vitro ubiquitination of alpha-synuclein fibrils recapitulated the pattern of alpha-synuclein ubiquitination observed in human disease and the A53T alpha-synuclein mouse model. These results suggest that ubiquitination of alpha-synuclein is not required for inclusion formation and follows the fibrillization of alpha-synuclein.     

Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication

Striatal nicotinic acetylcholine receptors with high affinity for nicotinic agonists are involved with the release of a number of neurotransmitters, including dopamine. Previous findings as to whether these receptors are changed in Parkinson's disease and Alzheimer's disease are inconsistent and no previous investigations have focused on these receptors in dementia with Lewy bodies and schizophrenia, which are also associated with disorders of movement. The present autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted with particular reference to the potentially confounding variables of tobacco use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral caudate and putamen was significantly reduced in Parkinson's disease (43-67%, n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%, n=20) compared to age-matched controls (n=42). Although tobacco use in the control group was associated with increased [3H]nicotine binding (21-38%), and neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was associated with reduced [3H]nicotine binding (up to 29%), differences between neurodegenerative disease groups and controls persisted in subgroups of Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had received no neuroleptic medication compared to controls who had not smoked (n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85 years) chronically medicated individuals with schizophrenia (n=6) was elevated compared with the entire control group (48-78%, n=42) and with a subgroup that had smoked (24-49%, n=8).The changes observed in [3H]nicotine binding are likely to reflect the presence of these receptors on multiple sites within the striatum, which may be differentially modulated in the different diseases. Further study is warranted to explore which nicotinic receptor subunits and which neuronal compartments are involved in the changes in [3H]nicotine binding reported, to aid development of potential nicotinic receptor therapy.     

Early-onset dementia with Lewy bodies

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.     

Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits

Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.     

Aggressive male APP23 mice modeling behavioral alterations in dementia

In addition to cognitive deterioration, Alzheimer's disease patients exhibit behavioral and psychological signs and symptoms of dementia. Behavioral alterations are a major source of caregiver stress and an important contributor in the decision to institutionalize patients. The amyloid precursor protein (APP) 23 transgenic mouse model develops amyloid plaques from the age of 6 months onward and exhibits tau pathology, which is absent in most other amyloid-based models. Besides mimicking the demented patients' memory deficits, these transgenic mice present with various behavioral disturbances, thereby approximating the clinical situation remarkably well. Using an isolation-induced/resident-intruder paradigm of aggression, the authors revealed increased aggressiveness in male APP23 mice at the ages of 6 and 12 months. The presence of aggressive disturbances in this valuable mouse model opens perspectives to evaluate aggression-modulating therapies.     

Impairment of the septal cholinergic neurons in MPTP-treated A30P α-synuclein mice

Dementia in Parkinson's disease (PDD) and dementia with Lewy bodies (DLB) are characterized by loss of acetylcholine (ACh) from cortical areas. Clinical studies report positive effects of acetylcholine esterase (AChE) inhibitors in PDD and dementia with Lewy bodies. We here report that the number of neurons expressing a cholinergic marker in the medial septum-diagonal band of Broca complex decreases in A30P α-synuclein-expressing mice during aging, paralleled by a lower AChE fiber density in the dentate gyrus and in the hippocampal CA1 field. After inducing dopamine depletion by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), no acute but a delayed loss of cholinergic neurons and AChE-positive fibers was observed, which was attenuated by L-3,4-dihydroxyphenylalanine (DOPA) treatment. Expression of nerve growth factor (NGF) and tyrosine receptor kinase A (TrkA) genes was upregulated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride-treated wild type mice, but not in A30P α-synuclein expressing animals. In contrast, upregulation of sortilin and p75^NTR genes was found in the A30P α-synuclein-expressing mice. These results suggest that dopamine deficiency may contribute to the impairment of the septohippocampal system in patients with PDD and that L-3,4-dihydroxyphenylalanine may not only result in symptomatic treatment of the akinetic-rigid syndrome but may also alleviate the degeneration of basal forebrain cholinergic system and the cognitive decline.     

Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies

Heat shock proteins (Hsps) facilitate refolding of denatured polypeptides, but there is limited understanding about their roles in neurodegenerative diseases characterized by misfolded proteins. Because Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy are alpha-synucleinopathies characterized by filamentous alpha-synuclein (alpha-syn) inclusions, we assessed which Hsps might be implicated in these disorders by examining human brain samples, transgenic mouse models, and cell culture systems. Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD. Hsp90 levels were most predominantly increased in PD brains, which correlated with increased levels of insoluble alpha-syn. These alterations in Hsp90 were recapitulated in a transgenic mouse model of PD-like alpha-syn pathologies. Cell culture studies also revealed that alpha-syn co-immunoprecipitated preferentially with Hsp90 and Hsc70 relative to other Hsps, and exposure of cells to proteasome inhibitors resulted in increased levels of Hsp90. These data implicate predominantly Hsp90 in the formation of alpha-syn inclusions in PD and related alpha-synucleinopathies.     

Comparison of Technetium-99m-MIBI imaging with MRI for detection of spine involvement in patients with multiple myeloma

Background

Lewy body disease is, after Alzheimer's disease, the second most common cause of senile degenerative dementia with progressive cognitive deterioration, fluctuation of cognitive and motoric functions and psychotic symptoms. It is characterized histologically by the occurrence of Lewy bodies in allocortical, neocortical and subcortical structures. The aim of this study was to measure the cortical glucose metabolism using FDG PET (2-[18F]fluoro-2-deoxy-D-glucose position emission tomography) compared to normal subjects.

Patients and Methods

Five patients (5 m, mean age 75 y) with clinically suspected diffuse Lewy body disease (DLB) were studied with FDG PET. PET studies of the head were performed with a Siemens ECAT-ART PET-scanner with attenuation correction using 137-Cs point sources.

Results

We found the same distribution pattern of diffuse glucose hypometabolism in the entire cortical region with relative sparing of the primary sensory-motor cortex in all the patients. The few cases reported in the literature so far describe findings similar to ours.

Conclusion

The pattern of diffuse glucose hypometabolism in the entire cortex including the occipital region seems to be a typical feature of DLB that is distinctive from dementia of Alzheimer's disease.     

Impaired long-trace eyeblink conditioning in a Tg2576 mouse model of Alzheimer's disease

Eyeblink conditioning has been used for assessing cognitive performance in cases of human neurodegenerative diseases including Alzheimer's disease (AD). Here, we tested and compared the delay and long-trace interval (TI = 500 ms) eyeblink conditionings in a Tg2576 mouse model of AD, at the age of 3, 6, and 12 months. Tg2576 mice exhibited significant impairment in trace conditioning at 6 months of age. In contrast, delay conditioning was not impaired in Tg2576 mice even at 12 months. These findings indicate that the long-TI eyeblink conditioning is more susceptible to age-related cognitive deterioration than delay conditioning in Tg2576 mice. The long-trace eyeblink conditioning could be a potential tool for detecting early cognitive deficits in AD mouse model.     

Intra- and intertask relationships in a behavioral test battery given to Tg2576 transgenic mice and controls

Several transgenic mouse models for Alzheimer's disease (AD) that develop -amyloid deposition have recently been advanced, including the Tg2576 mouse. Thorough behavioral phenotyping of this, or any mouse line/population, requires not only analysis of multiple behavioral measures through a comprehensive battery of tasks, but also a clear understanding of the interrelationships between behavioral measures in such a battery. In our accompanying study (King et al., this volume), Tg2576 transgenic (Tg+) and nontransgenic (Tg-) mice aged 3-19 months were administered an extensive behavioral test battery. The present study involved correlation analysis between those behavioral measures. Numerous correlations were evident for all 169 mice (Tg+ and Tg-) combined, with additional correlations being dependent on genotype or age. For all mice combined, intratask measures in water maze and circular platform were highly correlated; in addition, several measures of activity correlated with each other, as did various measures of balance/agility. A number of correlations between the six cognitive-based tasks of the test battery (e.g. Y-maze, Morris water maze, circular platform, visible platform, passive avoidance, and active avoidance) were also evident, as were correlations between cognitive and sensorimotor measures. In as much as some correlations were found to be exclusive to either Tg+ or Tg- animals alone, separate analysis by genotype is clearly warranted whenever two or more genotypes are involved. Likewise, some correlations were age-dependent, being present either in young adulthood (3 months) or in old age (19 months). These correlation analysis results in mice indicate that: (1) performance in one or several behavioral measures can be predictive of performance in others and (2) both genetic background and age influence the degree and profile of intra-/intertask relationships in an extensive behavioral test battery.     

Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease

The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.     

Memory Decline of Aging Reduced by Extracellular Superoxide Dismutase Overexpression

Extracellular superoxide dismutase (EC-SOD) plays an important role in controlling oxidative stress as well as intercellular signaling. In the current study, we tested the effect of EC-SOD overexpression over the lifespan of a set of mice and their wild-type controls to determine the time scale over which EC-SOD overexpression might attenuate aging-induced memory impairment. Mice with overexpression of EC-SOD and wild-type controls were initially trained on the radial-arm maze as young adults (3–5 months) and then retrained during middle age (12–14 months) and retested in old age at 27 and 30 months. There was little EC-SOD effect during the young adult middle age periods. EC-SOD overexpression prevented the decline in choice accuracy when the mice were 27–30 months of age. The EC-SOD overexpressing mice maintained their performance, while the wild-type mice declined to naïve levels of performance by 30 months of age. Enhancement of EC-SOD activity appears to improve memory performance specifically in aging mice. EC-SOD mimetic treatment during the course of aging may hold promise for aging-induced cognitive impairment.     

Early discrimination reversal learning impairment and preserved spatial learning in a longitudinal study of Tg2576 APPsw mice

To understand the relationship between amyloid-beta and cognitive decline in Alzheimer's disease, we evaluated cortical and hippocampal function in a transgenic mouse model of amyloid over-expression in Alzheimer's disease, the Tg2576 mouse. Tg2576 mice and their non-transgenic littermates were assessed at both 6 and 14 months of age in a battery of cognitive tests: attentional set-shifting, water maze spatial reference memory and T-maze working memory. Spatial reference memory was not affected by Tg status at either age. Working memory was only affected by age, with 6-month-old mice performing better than 14-month-old ones. Older mice were also significantly impaired on reversal learning and on the intra- and extra-dimensional shift in attentional set-shifting. A significant transgene effect was apparent in reversal learning, with Tg2576 mice requiring more trials to reach criterion at 6 months old. These data indicate that the effects of normal aging in C57B6xSJL F1 mice are most pronounced on putative frontal cortex-dependent tasks and that increasing Abeta load only affects discrimination reversal learning in our study.     

非阿尔茨海默型痴呆的病理诊断

目的认识非阿尔茨海默型痴呆的组织学特征和组织类型以及免疫组织化学在诊断中的意义。方法对22例尸检确诊的神经变性痴呆脑组织进行了Bodian、Gallyas—Braak染色,tau和泛素免疫组织化学染色,观察脑组织中神经元和胶质细胞包涵体的形态特征,分布和蛋白质表达活性。根据非阿尔茨海默型痴呆的组织学标准,结合临床进行病理诊断。结果22例神经变性痴呆中,12例诊断为非阿尔茨海默型痴呆。其中皮克病2例,进行性核上性麻痹和皮质基底节变性各3例,皮质型路易小体痴呆1例,帕金森病合并痴呆3例。其余10例中,9例诊断为单纯阿尔茨海默病,1例为阿尔茨海默病合并嗜银颗粒痴呆。在非阿尔茨海默型痴呆的脑组织观察到特征性神经元和胶质细胞包涵体,包括经典型和皮质型路易小体,皮克小体,球形团样神经原纤维缠结,星形细胞斑和葱状星形细胞,嗜银颗粒。除路易小体外,其他包涵体结构具有嗜银性;路易小体主要表达泛素,皮克小体可表达tau和泛素,而球形团样神经原纤维缠结、星形细胞斑、葱状星形细胞、嗜银颗粒仅对tau免疫染色敏感。结论采用Gallyas-Braak染色,tau和泛素免疫组织化学染色等新方法能够敏感地显示特征性神经元和胶质细胞包涵体,观察到这些神经元和神经胶质细胞包涵体可进一步明确非阿尔茨海默型痴呆的组织类型。     

Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias

Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer''s disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post‐mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson''s disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β‐amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post‐mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.     

Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin 1. To elucidate cellular pathways involved in SCA1, we used DNA microarrays to determine the pattern of gene expression in SCA1 transgenic mice at two specific times in the disease process; 5 weeks, a timepoint prior to onset of pathology, and 12 weeks, at the midpoint of the disease progression. Taking advantage of the availability of three SCA1 transgenic mouse lines, each expressing a different form of ataxin-1, we utilized a strategy that resulted in the identification of a limited number of genes with an altered pattern of expression specific to the development of disease. By comparing the pattern of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with those seen in two non-ataxic lines, A02-ataxin-1[30Q] and K772T-[82Q], nine genes were identified whose expression was consistently altered in the cerebellum of B05[82Q] mice at 5 and 12 weeks of age. Interestingly, five of the genes in this group form a biological cohort centered on glutamate signaling pathways in Purkinje cells.