Biomedical subjects

Jennifer Rodger

Publications and source records attributed to Jennifer Rodger.

8 recordsLinked to original sources

PubMed2026

Beyond enrichment: pharmacogenetic heterogeneity in treatment-resistant depression.

OBJECTIVES: Genetic variation has been proposed as a potential contributor to antidepressant nonresponse, but its role in treatment-resistant depression (TRD) remains unclear. This study used pharmacogenetics (PGx) to characterize genetic variation in TRD and determine whether actionable PGx variation and drug-gene interaction (DGI) mismatch were associated with antidepressant nonresponse and TRD burden. METHODS: This observational study included 158 individuals with TRD recruited from outpatient clinics in Western Australia. Genotype and genotype-predicted phenotypes for CYP2B6, CYP2C19, and CYP2D6 were derived from commercial PGx testing and compared with ethnicity-matched reference populations from ClinPGx. Antidepressant-specific DGIs were classified as actionable or nonactionable according to Clinical Pharmacogenetics Implementation Consortium guidelines, and unsupervised clustering was used to identify clusters based on these actionability profiles. Analyses were performed to determine if actionable PGx variation, cluster membership, or PGx mismatch was associated with TRD burden (number of failed antidepressant trials). RESULTS: PGx variation in the TRD cohort was consistent with population expectations, with no evidence of enrichment for actionable PGx variants. Clustering identified six clusters with distinct and gene-specific patterns of PGx variation independent of demographic and clinical characteristics. However, neither PGx mismatch nor cluster membership were associated with TRD burden. CONCLUSION: These findings suggest that actionable PGx phenotypes are neither enriched in TRD nor associated with greater TRD severity. Rather, the results indicate that TRD does not represent a single, unified PGx-predicted 'poor pharmacological responder' phenotype but instead reflects a biologically heterogeneous collection of distinct PGx profiles.

antidepressants↗

PubMed2006

Graded ephrin-A2 expression in the developing hamster superior colliculus.

During development, ephrin gradients guide retinal ganglion cell axons to their appropriate topographic locations in the superior colliculus (SC). Expression of ephrin-A2, assessed immunohistochemically in the developing hamster SC, revealed a rostral(low) to caudal (high) gradient that is most prominent at postnatal days P4 and P7 when topography is established. Double-labelling immunohistochemistry for ephrin-A2 and cell specific markers revealed that ephrin-A2 is expressed exclusively by a subset of neurons. The expression pattern has implications for mechanisms underlying establishment of topography during development and following injury.

Animals↗

PubMed2006

Differential expression of the NMDA NR2B receptor subunit in motoneuron populations susceptible and resistant to amyotrophic lateral sclerosis.

We have compared the expression pattern of NMDA receptor subunits (NR1 and NR2A-D) and NR1 splice variants (NR1-1a/1b,-2a/2b,-3a/3b,-4a/4b) in motor neuron populations from adult Wistar rats that are vulnerable (hypoglossal, XII) or resistant (oculomotor, III) to death in amyotrophic lateral sclerosis (ALS). The major finding was higher levels of expression of the NR2B subunit in the hypoglossal nucleus. Quantitative real-time PCR showed that NR1 was expressed at a greater level than any of the NR2 subunits (>15 fold greater, P<or=0.05, n = 11 animals), while conventional RT-PCR showed no difference in NR1 splice variant expression (with all variants except NR1-3 detected in both nuclei; n = 6 animals). Within III, the NR2B subunit was expressed 1.7 to 2.6-fold lower than the other NR2 subunits (P<or=0.05), while in XII all NR2 subunits were expressed at equal levels. When comparing levels between the 2 nuclei, mRNA for the NR2B subunit was expressed 2.1-fold higher in XII compared to III (P<or=0.05), while their was no difference in mRNA expression for the other subunits. Immunohistochemical analysis confirmed greater NR2B protein levels within individual hypoglossal neurons compared to oculomotor neurons (1.8-fold greater, P<or=0.05, n = 5 animals). Lower expression of the NMDA NR2B subunit may constitute one factor conferring protection to oculomotor neurons in ALS.

Alternative Splicing↗

PubMed2005

The balance of NMDA- and AMPA/kainate receptor-mediated activity in normal adult goldfish and during optic nerve regeneration.

Retinotectal topography is established during development and relies on the sequential recruitment of glutamate receptors within postsynaptic tectal cells. NMDA receptors underpin plastic changes at early stages when retinal ganglion cell (RGC) terminal arbors are widespread and topography is coarse; AMPA/kainate receptors mediate fast secure neurotransmission characteristic of mature circuits once topography is refined. Here, we have examined the relative contributions of these receptors to visually evoked activity in normal adult goldfish, in which retinotectal topography is constantly adjusted to compensate for the continual neurogenesis and the addition of new RGC arbors. Furthermore, we examined animals at two stages of optic nerve regeneration. In the first, RGC arbors are widespread and receptive fields large resulting in coarse topography; in the second, RGC arbors are pruned to reduce receptive fields leading to refined topography. Antagonists were applied to the tectum during multiunit recording of postsynaptic responses. Normal goldfish have low levels of NMDA receptor-mediated activity and high levels of AMPA/kainate. When coarse topography has been restored, NMDA receptor-mediated activity is increased and that of AMPA/kainate decreased. Once topography has been refined, the balance of NMDA and AMPA/kainate receptor-mediated activity returns to normal. The data suggest that glutamatergic neurotransmission in normal adult goldfish is dual with NMDA receptors fine-tuning topography and AMPA receptors allowing stable synaptic function. Furthermore, the normal operation of both receptors allows a response to injury in which the balance can be transiently reversed to restore topography and vision.

2-Amino-5-phosphonovalerate↗

PubMed2004

Characterisation of tectal ephrin-A2 expression during optic nerve regeneration in goldfish: implications for restoration of topography.

EphA receptors and their ligands the ephrin-As, expressed as retinal and tectal gradients, are required for the development of retino-tectal topography [Neuron 25 (2000) 563] and its restoration during goldfish optic nerve regeneration [Mol. Cell. Neurosci. 25 (2004) 56]. We have reported previously that, during regeneration, a transient EphA3/A5 gradient is formed by differential expression across the entire retinal ganglion cell (RGC) population [Neurosci. Abs. 33 (2003) 358.2; Exp. Neurol. 183 (2003) 593]. In retino-recipient tectal layers, ephrin-A2 is normally expressed by only a sub-population of cells, but during regeneration, there is a graded increase with more expressing cells caudally than rostrally [Exp. Neurol. 166 (2000) 196]. Here, we examine the characteristics of tectal ephrin-A2 expression during regeneration. We report that the level of ephrin-A2 expression is comparable for all ephrin-A2-positive cells in normal animals and during regeneration. Using double-labelling immunohistochemistry for ephrin-A2 and specific cell markers (NeuN for neurons, GA5 for astrocytes, NN-1 for microglia/endothelial cells and 6D2 for oligodendrocytes), we demonstrate that ephrin-A2-expressing cells, as in normal animals, are exclusively neuronal. Moreover, double labelling with BrdU showed that ephrin-A2 is expressed in resident cells and not those generated during optic nerve regeneration [Brain Res. 854 (2000) 178, 153 (1978) 345].

Animals↗

PubMed2003

A dorso-ventral gradient of Pax6 in the developing retina suggests a role in topographic map formation.

Expression of the transcription factor Pax6 was assessed immunohistochemically in embryonic chick retina during retino-tectal map formation. A low dorsal to high ventral gradient was found that correlated with expression of the axonal guidance cue EphB2. Furthermore, transfection of Pax6 into undifferentiated P19 cells up-regulated EphB2. The results raise the possibility that Pax6 is upstream of EphB2 and that its graded expression defines the dorso-ventral axis of the retino-tectal projection.

Animals↗

PubMed2003

Failure to form a stable topographic map during optic nerve regeneration: abnormal activity-dependent mechanisms.

Visually evoked responses in the optic tectum are mediated by glutamate receptors. During development, there is a switch from N-methyl-d-aspartate (NMDA)- to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated activity as the retinotectal map refines and visual function ensues. A similar pattern is seen in goldfish as the map refines during optic nerve regeneration. Here we examined glutamate receptors during optic nerve regeneration in the lizard, Ctenophorus ornatus, in which an imprecise retinotopic map forms transiently but degrades, leaving animals blind via the experimental eye. Receptor function was examined using NMDA and AMPA/kainate antagonists during in vitro tectal recording of visually evoked post-synaptic extracellular responses. Expression of NR1 (NMDA) and GluR2 (AMPA) receptor subtypes was examined immunohistochemically. In unoperated control animals, responses were robust and AMPA/kainate receptor-mediated. When the imprecise map was present, responses were difficult to evoke and insecure; periods of spontaneous activity as well as inactivity were also noted. Although AMPA/kainate-mediated activity persisted and GluR2 immunoreactivity increased transiently, NMDA receptor-mediated activity was also consistently detected and NR1 expression increased. In the long term, when the map had degraded, responses were readily evoked and predominantly AMPA/kainate receptor-mediated although some NMDA-mediated activity and NR1 expression remained. We suggest that the asynchronous activity reaching the optic tectum results in an inability to recapitulate the appropriate functional sequences of expression of NMDA and AMPA/kainate receptors necessary to refine the retinotectal map.

Animals↗

PubMed2003

Transient up-regulation of retinal EphA3 and EphA5, but not ephrin-A2, coincides with re-establishment of a topographic map during optic nerve regeneration in goldfish.

Eph tyrosine kinase receptors and their ligands, the ephrins, play a key role in the establishment of retinotectal topography during development. Tectal up-regulation of ephrin-A2 in goldfish, coincident with the reestablishment of a retinotectal map, suggests a similar role during optic nerve regeneration. Here we report a complementary study of EphA3, EphA5 and ephrin-A2 expression in the retina. EphA3 and EphA5 are transiently up-regulated as ascending naso-temporal gradients, whereas ephrin-A2 remains uniform. The expression profiles differ from those in developing chick and mouse, suggesting that different combinations of retinal Eph receptors and ligands can generate topographic guidance information.

Amacrine Cells↗