Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e. when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer’s and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer’s Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments.

The ability of amylin, a pancreatic b-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose selfadministration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.

BackgroundEmerging evidence suggests that fast-spiking (FS) interneurons are disrupted in multiple neuropsychiatric disorders including autism, schizophrenia, and bipolar disorder. FS cells, which are the primary source of synaptic inhibition, are critical for temporally organizing brain activity, regulating brain maturation, and modulating critical developmental periods in multiple cortical systems. Reduced expression of parvalbumin, a marker of mature FS cells, has been reported in individuals with schizophrenia and bipolar disorder and in mouse models of schizophrenia and autism. Although these results suggest that FS cells may be immature in neuropsychiatric disease, this possibility had not previously been formally assessed.MethodsThis study used time-course global expression data from developing FS cells to create a maturation index that tracked with the developmental age of purified cortical FS cells. The FS cell maturation index was then applied to global gene expression data from human cortex to estimate the maturity of the FS cell developmental program in the context of various disease states. Specificity of the index for FS cells was supported by a highly significant correlation of maturation index measurements with parvalbumin expression levels that withstood correction for multiple covariates.ConclusionsResults suggest the FS cell developmental gene expression program is immature in autism, schizophrenia, and bipolar disorder. More broadly, the current study indicates that cell-type specific maturation indices can be used to measure the maturity of developmental programs even in data from mixed cell types such as those found in brain homogenates.

A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

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