Normal learning and memory in Morris Water Maze and in fear conditioning but enhanced extinction of inhibitory avoidance in <i>Cyfip1</i> heterozygous mice.

<p>(<b>A</b>) Mice were tested using the Morris Water Maze. Time (s) to travel to the target platform was not significantly different between genotypes. (<b>B</b>) Mice were tested for fear conditioning, with mice receiving shocks at 120 and 180 seconds during training. Testing was performed 24 hours later, in the same test chamber, without footshock. (<b>C</b>) Inhibitory avoidance was measured by latency to enter the dark side of the box associated with prior shock. Extinction of inhibitory avoidance is enhanced in the heterozygotes. The lower panel shows the experimental design. WT, wildtype mice; Het, heterozygous mice; acq, acquisition; ext, extinction; IA, inhibitory avoidance. *, P = 0.027.</p

Basal synaptic properties and long-term potentiation are normal but long-term depression is enhanced in <i>Cyfip1</i> heterozygotes.

<p>(<b>A</b>) Hippocampal slices from 4–6 weeks old wildtype (WT) or Cyfip1 heterozygous (Het) mice were analyzed for baseline synaptic properties, determined by input/output function, representing the relationship between stimulus intensity and the size of the field EPSP slope. (<b>B</b>) Paired-pulse facilitation in the Schaffer collateral-commissural pathway is not different between genotypes over the test interpulse interval of 50 ms. (<b>C</b>) HFS-induced LTP was not significantly different between wildtype (WT) or <i>Cyfip1</i> heterozygous (Het) mice. (<b>D</b>) PP-LFS-induced LTD in <i>Cyfip1</i> heterozygous mice was significantly increased. Inset: Representative EPSP traces recorded before stimulation (arrow) or 60 min after stimulation in wildtype and heterozygous animals (scale: 10 ms and 0.5 mV).</p

DHPG-induced long-term depression is not dependent on protein synthesis or mammalian Target of Rapamycin in <i>Cyfip1</i> heterozygotes.

<p>(<b>A</b>) LTD was induced by DHPG (50 µM for 5 minutes, indicated by the short horizontal bar) in hippocampal slices from wildtype (Wt) and <i>Cyfip1</i> heterozygous (Het) mice. LTD is significantly enhanced in the heterozygotes as compared to wildtype. Inset: Representative EPSP traces recorded before (arrow) or 40 min after DHPG in wildtype and heterozygous animals (scale: 10 ms and 0.5 mV). (<b>B, C</b>) LTD was induced with DHPG in wildtype (B) or <i>Cyfip1</i> heterozygous (C) mice, in the absence (o) or presence (•) of cycloheximide (Cyclohex, 60 µM, indicated by the long horizontal bar). Cycloheximide significantly inhibited LTD in slices from wildtype but not heterozygous animals. (<b>D, E</b>) LTD was induced by DHPG (50 µM, indicated by the short horizontal bar) in hippocampal slices from wildtype (D) or <i>Cyfip1</i> heterozygous (E) mice, in the absence (o) or presence (•) of rapamycin (20 nM, indicated by the long horizontal bar). (<b>F</b>) LTD was induced by DHPG (50 µM, indicated by the short horizontal bar) in hippocampal slices from wildtype (o) or <i>Cyfip1</i> heterozygous (•) mice, the latter in the absence (•) or presence (▪) of both MPEP (10 µM) and LY367385 (indicated by the long horizontal bar). Application of the mGluR1 and mGluR5 antagonists decreased the magnitude of DHPG-induced-LTD in heterozygotes.</p

Generation and characterization of a mouse with disruption of the <i>Cyfip1</i> gene.

<p>(<b>A</b>) The genomic structure of <i>Cyfip1</i> is shown to scale with larger horizontal boxes representing exons, and the first (ATG) and last (Stop) coding exons indicated. The diagram shows the site of the gene-trap insertion (identified as an LTR-flanked Trapping casette) in intron 1 (5′ to the first coding exon), in order to generate mice with a disruption of the <i>Cyfip1</i> gene. (<b>B</b>) Synaptoneurosome preparations from wildtype (Wt) and <i>Cyfip1</i> heterozygous (Het) mice were subjected to quantitative immunoblotting with an antibody to Cyfip1, with actin as a reference protein. The migration of molecular weight markers is shown on the left (in kDa). (<b>C</b>) Brain mRNA from wildtype (black bars) and <i>Cyfip1</i> heterozygous (white bars) mice were subjected to qPCR for the indicated genes. (<b>D</b>) Quantification of Cyfip1 and Fmrp by immunoblotting of extracts from wildtype (black bars) and heterozygous (white bars) mice. *, P<0.05; **, P = 0.004.</p