The mGluR5-receptor antagonist MPEP attenuates elevated repetitive behaviors in mice exposed to valproic acid (VPA) <i>in utero.</i>

<p>(<b>A</b>) Repetitive self-grooming was measured over 10 minutes in mice exposed to prenatal saline (SAL) or VPA. (<b>B</b>) Repetitive marble burying behavior was measured for both groups after a 30 minute testing session. Across both assays, VPA-exposed mice demonstrated elevated stereotyped, repetitive behaviors that were significantly reduced by MPEP. Figures show mean ± S.E.M., (*<i>p</i><0.05, **<i>p</i><0.01).</p

The effect of MPEP was assessed on anxiety-like behavior in VPA- and SAL-exposed mice using an open-field paradigm.

<p>Consistent with elevated anxiety, VPA-exposed mice demonstrated significantly fewer (<b>A</b>) center entries and qualitatively reduced (<b>B</b>) center time. Across groups, there was no effect of MPEP on either of these measures. Figures show mean ± S.E.M., (#<i>p</i><0.1, *<i>p</i><0.05).</p

Measuring the Maturity of the Fast-Spiking Interneuron Transcriptional Program in Autism, Schizophrenia, and Bipolar Disorder

<div><h3>Background</h3><p>Emerging 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.</p> <h3>Methods</h3><p>This 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.</p> <h3>Conclusions</h3><p>Results 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.</p> </div

FS cell maturation index in developing FS cells.

<p>Panel (a) is a line plot of FS cell postnatal age (x-axis) versus the FS cell index (y-axis) in purified developing FS cells. Panel shows that the FS cell index increases with age. Panel (b) is a linear regression of parvalbumin expression levels versus the FS cell index. Index measurements and parvalbumin levels were highly correlated in developing FS cells (R² = 0.95). Parvalbumin expression levels were excluded from the calculation of the FS cell index.</p

FS cell index applied to typically developing prefrontal cortex.

<p>Panel (a) is a linear regression of FS cell index measurements from developing human prefrontal cortex versus post-gestational age (log2 years). Panel shows that the FS cell index increases with age. Panel (b) is a linear regression of the FS cell index versus parvalbumin expression levels in developing prefrontal cortex. Panel shows that parvalbumin levels were closely related to FS cell index measurements even in data from heterogeneous tissue. Parvalbumin expression levels were excluded from the calculation of the FS cell index.</p

FS cell index versus parvalbumin expression levels in gene expression studies of neuropsychiatric disease.

<p>Panels (a–c) are linear regression plots of the FS cell index versus parvalbumin expression levels in 3 separate studies of global gene expression in autism(a), schizophrenia(b), and bipolar disorder(c). Panels show that the relationship between FS cell index measurements and parvalbumin levels is robust across studies and micoarray platforms. Parvalbumin expression levels were excluded from the calculation of the FS cell index.</p

Multiple linear regression - Human prefrontal cortex development.

<p>FS = FS cell index.</p><p>CSP = Corticospinal projection neuron index.</p><p>AST = Astrocyte index.</p><p>The first 3 tables show simple linear regression of 3 maturation indices (FS cell index, Corticospinal projection neuron index, and Astrocyte index) on parvalbumin expression levels in data from developing human prefrontal cortex. In all cases there was a highly significant relationship between index measurements and parvalbumin expression levels (p<0.0001). The fourth table shows results when all three indices were entered in the same model. Only the FS cell index remained significantly associated with parvalbumin expression levels (p<0.002).</p

FS cell index in psychiatric disorders.

<p>Panels (a–c) are bar graphs of the FS cell index in the cortex of controls and individuals with disease. Panels show that the FS cell index was decreased in the cortex in autism, schizophrenia, and bipolar disorder. Panels (d–f) are bar graphs of parvalbumin levels in the cortex of controls and individuals with disease. Panels show that parvalbumin levels were decreased in the cortex in autism, schizophrenia, and bipolar disorder. Parvalbumin expression levels were excluded from the calculation of the FS cell index. ** p<0.01, ***p<0.001 n = number of subjects.</p