16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development.

Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of 'footprint'-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information-available with the cell lines by request from the Simons Foundation Autism Research Initiative-with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

Indomethacin Increases Neurogenesis across Age Groups and Improves Delayed Probe Trial Difference Scores in Middle-Aged Rats.

We tested whether indomethacin or rosiglitazone treatment could rejuvenate spatial ability and hippocampal neurogenesis in aging rats. Young (4 mo; n = 30), middle-aged (12 mo; n = 31), and aged (18 mo; n = 31) male Fischer 344 rats were trained and then tested in a rapid acquisition water maze task and then fed vehicle (500 µl strawberry milk), indomethacin (2.0 mg/ml), or rosiglitazone (8.0 mg/ml) twice daily for the remainder of the experiment. A week after drug treatment commenced, the rats were given 3 daily BrdU (50 mg/kg) injections to test whether age-related declines in neurogenesis were reversed. One week after the final BrdU injection (~2.5 weeks after the 1st water maze session), the rats were trained to a find novel hidden water maze platform location, tested on 15 min and 24 h probe trials and then killed 24 h later. During the first water maze session, young rats outperformed aged rats but all rats learned information about the hidden platform location. Middle-aged and aged rats exhibited better memory probe trial performances than young rats in the 2nd water maze session and indomethacin improved memory probe trial performances on the 2nd vs. 1st water maze session in middle-aged rats. Middle-aged rats with more new neurons had fewer phagocytic microglia and exhibited better hidden platform training trial performances on the 2nd water maze session. Regardless of age, indomethacin increased new hippocampal neuron numbers and both rosiglitazone and indomethacin increased subependymal neuroblasts/neuron densities. Taken together, our results suggest the feasibility of studying the effects of longer-term immunomodulation on age-related declines in cognition and neurogenesis.

Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats.

We trained and tested young (6-8months; n=13), middle-aged (12-14months; n=41), and aged (22-24months; n=24) male Fischer 344 rats in a rapid acquisition water maze task and then quantified 27 stress hormones, cytokines and chemokines in their serum, hippocampi and frontal cortices using bead assay kits and xMAP technology. Middle-aged and aged rats learned the location of the hidden platform over training trials more slowly than their young counterparts. After training, young rats outperformed middle-aged and aged rats on both immediate and 24h retention probe trials and about half of the middle-aged and aged (aging) rats exhibited impaired performances when tested on the retention probe trial 24h later. The concentrations of many serum, hippocampal and cortical analytes changed with age often in networks that may represent age-sensitive signaling pathways and the concentrations of some of these analytes correlated with water maze learning and/or memory scores. Serum GRO/KC and RANTES levels, hippocampal GM-CSF levels and cortical IL-9 and RANTES levels were significantly higher in rats categorized as memory-impaired versus elite agers based upon their 24h probe trial performances. Our data add to the emerging picture of how age-related changes in immune and neuroimmune system signaling impacts cognition.

Desvenlafaxine may accelerate neuronal maturation in the dentate gyri of adult male rats.

Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5-6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies.

PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness.

The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused an ∼50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.