Faculty Bibliography

Abstract Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages

The electrophysiological properties of rat inferior olive (IO) neurons in the dorsal cap of Kooy (DCK) and the adjacent ventrolateral outgrowth (VLO) were compared with those of IO neurons in the principal olive (PO). Whereas DCK/VLO neurons are involved in eye movement control via their climbing fiber projection to the cerebellar flocculus, PO neurons control limb and digit movements via their climbing fiber projection to the lateral cerebellar hemisphere. In vitro patch recordings from DCK/VLO neurons revealed that low threshold calcium currents, Ih currents, and subthreshold oscillations are lacking in this subset of IO neurons. The recordings of activity in DCK neurons obtained by using voltage-sensitive dye imaging showed that activity is not limited to a single neuron, but rather that clusters of DCK neurons can be active in unison. These electrophysiological results show that the DCK/VLO neurons have unique properties that set them apart from the neurons in the PO nucleus. This finding indicates that motor control, from the perspective of the olivocerebellar system, is fundamentally different for the oculomotor and the somatomotor systems

Myotubularins (MTM) are a large subfamily of lipid phosphatases that specifically dephosphorylate at the D3 position of phosphatidylinositol 3-phosphate (PI(3)P) in PI(3)P and PI(3,5)P2. We recently found that MTMR6 specifically inhibits the Ca2+-activated K+ channel, KCa3.1, by dephosphorylating PI(3)P. We now show that inhibition is specific for MTMR6 and other MTMs do not inhibit KCa3.1. By replacing either or both of the coiled-coil (CC) and pleckstrin homology/GRAM (PH/G) domains of MTMs that failed to inhibit KCa3.1 with the CC and PH/G domains of MTMR6, we found that chimeric MTMs containing both the MTMR6 CC and PH/G domains functioned like MTMR6 to inhibit KCa3.1 channel activity, whereas chimeric MTMs containing either domain alone did not. Immunofluorescent microscopy demonstrated that both the MTMR6 CC and PH/G domains are required to co-localize MTMR6 to the plasma membrane with KCa3.1. These findings support a model in which two specific low affinity interactions are required to co-localize MTMR6 with KCa3.1: 1) between the CC domains on MTMR6 and KCa3.1 and (2) between the PH/G domain and a component of the plasma membrane. Our inability to detect significant interaction of the MTMR6 G/PH domain with phosphoinositides suggests that this domain may bind a protein. Identifying the specific binding partners of the CC and PH/G domains on other MTMs will provide important clues to the specific functions regulated by other MTMs as well as the mechanism(s) whereby loss of some MTMs lead to disease

BACKGROUND: Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central alpha1-adrenoceptor action. METHODS: Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with alpha1-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis). RESULTS: Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas. CONCLUSIONS: The results support the hypothesis that immune activation reduces alpha1-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness

Piriform cortical circuits are hypothesized to form perceptions from responses to specific odorant features, but the anterior piriform cortex (aPCX) and posterior piriform cortex (pPCX) differ markedly in their anatomical organization, differences that could lead to distinct roles in odor encoding. Here, we tested whether experience with a complex odorant mixture would modify encoding of the mixture and its components in aPCX and pPCX. Rats were exposed to an odorant mixture and its components in a go/no-go rewarded odor discrimination task. After reaching behavioral performance criterion, single-unit recordings were made from the aPCX and pPCX in these rats and in odor-naive, control, urethane-anesthetized rats. After odor experience, aPCX neurons were more narrowly tuned to the test odorants, and there was a decorrelation in aPCX population responses to the mixture and its components, suggesting a more distinct encoding of the familiar mixture from its components. In contrast, pPCX neurons were more broadly tuned to the familiar odorants, and pPCX population responses to the mixture and its components became more highly correlated, suggesting a pPCX encoding of similarity between familiar stimuli. The results suggest aPCX and pPCX play different roles in the processing of familiar odors and are consistent with an experience-dependent encoding (perceptual learning) of synthetic odorant identity in aPCX and an experience-dependent encoding of odor similarity or odor quality in pPCX

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1alpha gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1alpha gene expression. Crossbreeding of PGC-1alpha knockout (KO) mice with HD knockin (KI) mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1alpha partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1alpha in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1alpha in the control of energy metabolism in the early stages of HD pathogenesis