Schematic of the <i>Dnm1</i> transcript and the conditional EE genotype strategy.

<p>(Top) The <i>Dnm1</i>^<i>Ftfl</i> allele is shown with the mutation in alternatively spliced exon 10a. (Middle) The <i>Dnm1</i>^<i>flox</i> allele is shown with location of the loxP sites flanking exons 2–4 [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005347#pgen.1005347.ref007" target="_blank">7</a>]. (Bottom) After cre recombinase activity, exons 2–4 are deleted resulting in a frameshift and the <i>Dnm1</i>^<i>null</i> allele. Thus, the genotypes in the present studies are compound heterozygous, <i>Dnm1</i>^{<i>Ftfl/null</i>}, where the null (deleted allele) is present only in cells that express cre recombinase.</p

Expression patterns associated with cre recombinase mouse lines used in this study.

<p>The first 5 cre lines are inhibitory neuron targeted and the <i>Emx1</i> line is excitatory neuron expressed. References detailing the creation and characterization of the lines follow each cre line name. The + and–symbols are used to represent relative expression ranging from high (++++) to none observed (-). Timing indicates when the cre is first observed to express and where if isolated expression is observed initially.</p><p>Expression patterns associated with cre recombinase mouse lines used in this study.</p

Altered dopaminergic and glutamatergic response.

<p>Hyperactivity induced by amphetamine (top graphs; males left, females right) or by challenge with MK-801 (bottom graphs; males left, females right) as measured by total distance traveled in the open field after administration of drug. Two-way repeated measures ANOVA (time x same sex genotype) with Bonferroni post-hoc comparisons (***P<0.001, *P<0.05).</p

Reduced lifespan of <i>Dnm1</i>^{<i>Ftfl/flox</i>} mice crossed to different Cre driver lines.

<p>Survival curves of <i>Dnm1</i>^{<i>Ftfl/flox</i>} mice in conjunction with specific cre driver lines from postnatal day 0 until day 180. 100% of the <i>Gad2</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice, 100% of the <i>Dlx5/6</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice and 91% of the <i>Pvalb</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice die before weaning. The <i>Emx1</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice do not have a reduced lifespan.</p

Summary of the effects of each cre line in combination with the <i>Dnm1</i>^{<i>Ftfl/flox</i>} genotype.

<p>Summary of the effects of each cre line in combination with the <i>Dnm1</i>^{<i>Ftfl/flox</i>} genotype.</p

<i>Emx1</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice demonstrate hyperactivity, stereotypical and altered activity.

<p>(A) Total distance traveled in the open field test, males on left, females on right. ****P<0.0001; two-way repeated measures ANOVA, Bonferroni post hoc analysis. (B) Vertical activity (rearing) in the open field test; males on left, females on right. One Way ANOVA with Dunnett’s post hoc test (***P<0.001, **P<0.01; vs WT control). (C) Repetitive behavior as measured by rotational behavior in the open field; males on left, females on right. One-way ANOVA (within sex) with Dunnett’s post-hoc test (****P<0.0001 vs WT control). (D) Activity measured in the wheel running assay. Total distance traveled (RPMs) was measured in 60 min time bins over a 48 hour period. Light/dark cycle is indicated below; males on left, females on right.</p

Dynamin 1 mutant genotypes referenced in this study.

<p>N.A., not applicable.</p><p>The first row indicates the name of the mouse line referred to in the study. The <i>Dnm1</i> genotype indicates the composition of the two dynamin-1 alleles for that mouse line and is followed by the reference which created or characterized the mouse or allele. The table describes the seizure and behavior phenotypes for the particular mouse line/dynamin allele combination.</p><p>Dynamin 1 mutant genotypes referenced in this study.</p

Structure of DNM1.

<p>Schematic of DNM1 protein showing the domain locations of eight human variants [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005347#pgen.1005347.ref001" target="_blank">1</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005347#pgen.1005347.ref003" target="_blank">3</a>] and the fitful mutation ([<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005347#pgen.1005347.ref005" target="_blank">5</a>]; in red) within an alternatively spliced exon in the middle domain. The exon structure shows the location of the fitful mutation in the alternatively spliced exon 10a. Dnm1a, containing exon 10a, and Dnm1b, containing exon10b, can functionally compensate for each other.</p

Anxiety- and depression-related behaviors of <i>Emx1</i>-cre;<i>Dnm1</i>^{<i>Ftfl/flox</i>} mice.

<p>(A) Amount of time spent at the perimeter was measured in the open field for 30 min; males on left, females on right. (B) Immobility time (sec) was measured in the tail suspension test; males on left, females on right. One-way ANOVA (within sex) with Dunnett’s post hoc analysis (****P<0.0001, **P<0.01, *P<0.05; v WT control).</p