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Fishing Expedition Yields Pro-neurogenesis Elixir for NPAS3 Mice

Adapted from a story that originally appeared on the Alzheimer Research Forum.

19 August 2010. Scientists on an optimistic fishing expedition, involving 1,000 small molecules and hundreds of mice, have caught a big one with a chemical that promotes adult neurogenesis in mice missing the NPAS3 gene. Researchers from the University of Texas Southwestern Medical Center in Dallas report in the July 9 Cell that their compound, designated P7C3, enhances survival and integration of new hippocampal neurons, as well as memory, in mice and rats.

For schizophrenia researchers, the report by Andrew Pieper, Steven McKnight, and colleagues is of special interest because much of the work was done in transgenic mice with knocked out NPAS3, a gene associated with schizophrenia, bipolar disorder, and mental retardation. The study also extends the group's characterization of adult hippocampal neurogenesis deficits in these animals, and presents new data on abnormal granule cell morphology and synaptic transmission.

“Every day of our lives, in the hippocampus, we make thousands of cells,” Pieper said. Yet most of these new neurons die within four weeks of being born, for unknown reasons. Keeping them alive could bring potential dividends for neurodegenerative disorders, such as Alzheimer disease, which seems to impair neurogenesis (see He and Shen, 2009), not to mention schizophrenia, in which there is evidence—albeit imcomplete—for impaired neurogenesis (e.g., Reif et al., 2006). Currently, there is no drug on the market that specifically promotes neurogenesis, Pieper said, and previous in vitro screens have failed to yield compounds effective in animals. Therefore, the researchers decided to screen small molecules in mice. They were not at all sure they would find any promising compounds, but reasoned that if they were lucky enough to do so, they would already have something effective in vivo.

McKnight and colleagues divided their 1,000 potential drugs into 100 pools of 10 and treated mice with the cocktails. They injected the mice with BrdU to label newly divided cells, and looked for growth in this population in the hippocampus. After separating the effective pools into individual components, the researchers discovered eight chemicals that boosted new neuron numbers. Pieper and colleagues then focused on one particular molecule—dubbed P7C3 for pool 7 compound3—because it was orally bioavailable, crossed the blood-brain barrier, and appeared to be non-toxic to the animals.

The NPAS3 model
P7C3 enhanced neurogenesis in wild-type animals, but the researchers wondered if it could also assist new neuron formation in mutant mice with impaired neurogenesis. They focused on the model lacking NPAS3, a transcription factor that controls adult neurogenesis. In earlier work, Pieper, McKnight, and colleagues discovered an almost complete absence of adult hippocampal neurogenesis in mice lacking the gene (Pieper et al., 2005). Like DISC1, the most well-known schizophrenia candidate gene, NPAS3 was originally identified as a schizophrenia candidate gene by old-fashioned karyotyping to look for chromosomal abnormalities in a mother and daughter with schizophrenia (see SRF related news story; see SZGene entry). Diane Cox of the University of Alberta, Canada, and colleagues discovered a translocation (a “trade” of genomic segments) between chromosomes 9 and 14, that disrupted NPAS3 in the 14q13 region (Kamnarasan et al., 2003). This region, or the gene itself, has been implicated in a variety of studies of schizophrenia and bipolar disorder, particularly in syndromes that include intellectual disability (reviewed in a recent positive association study by Cox and colleagues: Macintyre et al., 2010). In the current study, the researchers determined that the neurogenesis deficit in mice without NPAS3 is not due to a lack of proliferation. Rather, animals lacking the transcription factor are able to form neural precursor cells, but the cells do not survive the maturation process. "This enhanced level of apoptosis is likely to account, at least in part, for the nearly complete elimination of adult neurogenesis in NPAS3-/- mice," they write. The mutant mice also have other deficits, Pieper and colleagues report, including reduced dendritic branching and dendritic spine density, as well as "aberrant hyperexcitability of synaptic transmission…both in the outer molecular layer of the dentate gyrus and in the CA1 region of the hippocampus." Promisingly, P7C3 administered continuously to NPAS3 knockout mice after prenatal day 14 (either via the mother or, after weaning, directly) helped rescue many of the structural and functional abnormalities in the dentate gyrus in these animals.

Improving cognition
There is evidence that neurogenesis enhances cognition and memory (see Clelland et al., 2009), But unfortunately, the researchers were not able to link up the hippocampal deficits of the NPAS3 mutant mice with cognition, as these animals are unable to swim and thus cannot be tested in the classic Morris water maze. The behavioral experiments were performed instead in 18-month-old wild-type rats, who were treated with P7C3 before testing them in a water maze. “Aged rats have difficulty with tasks of learning and memory,” Pieper said. Drug- and vehicle-treated animals were equally able to learn the location of a raised platform in the pool. Then, the scientists removed the platform to test how well the rats recalled its former location. Compared to the control, vehicle-treated animals, the P7C3-treated rats spent more time swimming over where the platform used to be, suggesting enhanced learning and memory. The study “really strengthens the connections between adult neurogenesis and cognitive function,” said Henriette van Praag of the National Institute on Aging in Bethesda, Maryland, who was not involved in the work.

How does P7C3 rescue newborn neurons? Normally, many of these cells undergo apoptosis, a process regulated by mitochondria. The researchers used cultured U2OS cells, a human osteosarcoma line, to examine mitochondrial permeability under P7C3 treatment. They put the cells under high calcium conditions, to stress them, with a dye that leaks out of the organelle in the presence of excess calcium. P7C3 prevented the dye’s release from mitochondria, suggesting it helps maintain the organelle’s membranes. Similar effects were found in cultured neurons. This action is similar, the authors note, to a possible mitochondria-sealing mechanism of Dimebon, a candidate drug for Alzheimer disease (Zhang et al., 2010; Bachurin et al., 2003). The most recent trial results for Dimebon were poor, but the authors suggest it might be possible to enhance its efficacy or potency. If so, the assays in their study could be useful to test Dimebon derivatives, they wrote.

“We do not know yet what the actual target of [P7C3] is,” Pieper said “It enhances the stability of the mitochondria.” The researchers are working to discover P7C3’s mechanism, and also plan to test the compound in mouse models for Alzheimer’s, Huntington disease, spinocerebellar atrophy, and amyotrophic lateral sclerosis.—Amber Dance and Hakon Heimer.

Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51. Abstract

Q&A With Andrew Pieper. Questions by Hakon Heimer.

SRF: From the point of view of schizophrenia research, the further characterization of the NPAS3 mice would seem to be the starting point of interest in this paper. Is that accurate, and how do you see these new data on the pathophysiology being interpreted and further explored?

AP: Actually, Hakon, I believe that the main story here for schizophrenia is that we have discovered pro-neurogenic, neuroprotective agents that may serve as a basis for developing new treatment strategies that target the cognitive symptoms of schizophrenia.

With respect to the NPAS3 model itself, we had previously shown that these mice suffer an 84 percent reduction in adult hippocampal neurogenesis, and now we have found out that this decrease is due to elevated levels of apoptosis of newborn hippocampal neurons. The same number of neural precursor cells are born within the subgranular zone of the dentate gyrus of the hippocampus in adult NPAS3-deficient mice, but more of the newborn cells die. Also, we have more fully characterized morphological and electrophysiological deficits in the dentate gyrus of these mice. We were very excited to see that prolonged administration of P7C3 to NPAS3-deficient mice effectively normalized the level of apoptosis of newborn hippocampal neural precursor cells, and fixed the functional and structural deficits in the dentate gyrus of these mice.

Unfortunately, due to other physical problems inherent to NPAS3-deficient mice, they are incapable of swimming, and thus cannot be evaluated in the standard assay for hippocampus-dependent learning, the Morris water maze task. As such, we turned to aged rats to directly assess the potential benefits of P7C3 on hippocampus-dependent learning. Normal rodent aging is associated with diminished hippocampal neurogenesis, also likely related to elevated apoptosis of newborn hippocampal neural precursor cells. These changes have been proposed to contribute to cognitive decline in aging, and we saw that prolonged administration of P7C3 to aged rats effectively enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved performance in the Morris water maze. We are, of course, also looking forward to evaluating the effects of P7C3 on cognition in animal models of schizophrenia other than the NPAS3-deficient mice.

SRF: Do you see these results dovetailing in any way with other research on ontogenetic or adult neurogenesis? I'm thinking particularly of the work with DISC1, but perhaps there is other work you know of.

AP: We certainly see many opportunities for integrating this work with other scientific findings on neurogenesis throughout the lifespan. This would include DISC1 as well as other animal models of schizophrenia or neuropsychiatric disease.

SRF: Do you know of any evidence for increased apoptosis in human progenitor cells in schizophrenia or bipolar disorder?

AP: The progressive clinical deterioration and neurostructural changes in the brain frequently seen in schizophrenia or severe forms of bipolar disorder have led to the hypothesis that aberrantly regulated apoptosis may contribute to the pathophysiology of these diseases. This is an active area of investigation in many laboratories and clinics around the world, and some evidence suggests that this may indeed be the case in some patients.

SRF: What would be needed in terms of follow-up for this compound or ones like it to be used in schizophrenia?

AP: While we're optimistic about the prospects for P7C3, there remains considerable research and testing to do first. If this works out as we hope, there eventually will be patient trials and so forth. We don't know how long this will take, but probably several years.

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