Developmental changes in the composition of NMDA receptors can alter receptor physiology as well as intracellular signal transduction cascades, potentially shifting thresholds for neural and behavioral plasticity. During song learning in zebra finches, NMDAR currents become faster, and transcripts for the modulatory NR2B subunit of this receptor decrease in lMAN, a region in which NMDAR activation is critical for vocal learning. Using in situ hybridization, we found that NR2A transcripts change reciprocally, increasing significantly in both lMAN (59%) and in another song region, Area X (38%), between posthatch day (PHD) 20 and 40, but not changing further at PHD60 or 80. In adjacent areas not associated with song learning, NR2A mRNA did not change between PHD20-80. Although early song deprivation (which extends the sensitive period for song learning) delays changes in NR2B gene expression and NMDAR physiology within the lMAN, it did not alter NR2A mRNA levels measured at PHD40, 45, or 60. Early testosterone (T) treatment, which disrupts vocal development and accelerates the maturation of both NR2B levels and NMDAR physiology in lMAN, also significantly increased NR2A transcripts measured at PHD35 in lMAN. In Area X, a similar effect of T approached significance. Together with our previous studies, these results show that in a pathway critical for vocal plasticity, the ratio of NR2A:NR2B mRNA rises abruptly early during the sensitive period for song learning. Furthermore, androgen regulation of NMDAR gene expression may alter thresholds for experience-dependent synaptic change.

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Developmental changes in the composition and function of N-methyl-D-aspartate receptors (NMDARs) are believed to regulate neural plasticity. For example, in songbirds, vocal learning entails NMDAR activation, and the sensitive period for such learning in zebra finches (ZFs) parallels developmental changes in NMDAR density and phenotype within several song-related brain regions. In contrast to ZFs, canaries exhibit vocal plasticity recurrently throughout adulthood, prompted by seasonal changes in day length and testosterone (T) levels. We used in situ hybridization to determine if such changes in photoperiod affect NMDAR subunit expression in adult canaries. Birds were sacrificed while on short days (SD) when T levels were low, or on long days (LD) when T levels were high. Transcript levels for the constitutive NMDAR subunit (NR1) and two modulatory subunits (NR2A, NR2B) were measured in four song control nuclei: lMAN, Area X, HVc, and RA. NR1 and NR2A mRNA levels were comparable in SD and LD groups in all four song regions studied. However, NR2B mRNA levels within lMAN and RA were significantly higher in SD than in LD birds. Photoperiod did not affect NR2B transcript levels in Area X, HVc, or a nonsong region just lateral to lMAN. Our data support the hypothesis that changes in NMDAR subunit expression may contribute to the neural and behavioral reorganization that accompanies seasonal song remodeling in adulthood.

Most tumors, including prostate carcinoma, are heterogeneous mixtures of neoplastic cells and supporting stromal matrix. Attempts to vaccinate as a means to treat or prevent cancer have typically relied on use of a single antigen or cell type. In the case of whole-cell vaccines, clonal populations of cancer cells are grown in culture and harvested for vaccine material. However, it is clear from microarray data that neoplastic cells grown in culture are greatly different from those found in vivo. Tissue vaccines are harvested directly from tumors and are used to immunize the animal or the patient. They are antigenically rich, in that they are comprised of not only neoplastic cells but also supporting stromal matrix; furthermore, they include antigens that may be expressed only in vivo and which may be critical to a successful immune response to the cancer. For these reasons, the idea that tissue vaccines for cancer have potentially great utility has merit and should be explored further.

Reducing expression of the tissue factor gene in prostate adenocarcinoma cells (PAIII) results in a cell line that, in vivo, mimics the growth of wildtype (wt) PAIII. However, instead of continuing to grow and metastasize as wt PAIII tumors do, tissue factor deficient PAIII (TFD PAIII) masses spontaneously regress after several weeks. Although whole cell vaccines are typically inactivated prior to administration to prevent proliferation within the host, numerous studies have suggested that exposure to live, attenuated, whole tumor cells, and the extracellular microenvironment they recruit, increases immunotherapeutic potential. Here, we provide support for this notion, and a strategy through which to implement it, by demonstrating that subcutaneous vaccinations with the TFD PAIII protect the Lobund-Wistar rat against subsequent wt PAIII cell challenge. TFD PAIII immunized rats suffered significantly less metastasis of wt PAIII challenge tumors compared to unvaccinated naïve controls rats. These results offer the intriguing possibility that the TFD PAIII vaccine is an effective system for the prevention and, possibly, the treatment of prostate cancer.