Article Figures & Data
Figures
- Figure 1.
Arg deficiency redirects postnatal dendritic spine refinement. a, Dendritic spines were enumerated in layer V oPFC at P21, P24, P31, and P56–P60. Spine density peaked at P31 and then declined as control animals entered adulthood. In arg−/− mice, however, spine density dropped precipitously at P31 and remained low. Densities did not differ between arg−/− and wild-type cells at P21 and P24. Inset, Plate from Franklin and Paxinos (2007) at bregma 2.58 with oPFC sampling sites represented by black boxes. b, Representative oPFC dendrites with ages and genotypes indicated. Scale bars, 10 μm. c, In rostral CA1, wild-type spine density increased across postnatal development, but again, densities in arg−/− mice diverged at P31 and remained low at P56–P60. Inset, Plate at bregma −1.7 with black boxes representing sampling sites. d, Hippocampal spine density was analyzed as a function of distance from the somatic layer, revealing nonselective loss at P31. By P56–P60, loss was concentrated to a region 200–350 μm from the cell body layer. A dashed line was placed at 1.5 to facilitate comparison between plots. e, Dendritic spine lengths were also measured at P31 (adolescence) and P56–P60 (early adulthood). Cortical spines in adolescent arg−/− mice were longer than control spines at the same age, suggestive of an immature phenotype; consistent with this interpretation, spine head widths were also smaller in adolescent arg−/− mice (inset). These phenotypes appeared transient, however, since differences were not detected at P56–P60 (or P21 and P24) (data not shown). Hippocampal spine lengths did not differ between genotypes at any time point. f, Representative hippocampal dendrites with ages and genotypes indicated. Scale bars, 5 μm. Symbols represent means + SEMs. *p < 0.05; **p < 0.0001.
- Figure 2.
Arg regulates the psychomotor and cytoskeletal response to cocaine. a, The locomotor response to repeated cocaine exposure in wild-type and arg−/− mice did not differ when cocaine was administered from P24 to P28, before arg−/− spine loss. When mice were administered cocaine starting at P31, however, arg−/− mice were hypersensitive. Locomotor activity is normalized to drug-free baseline. b, Mice of both genotypes exposed to cocaine from P31–P35 showed heightened locomotor sensitivity to an acute cocaine challenge as 9-week-old adults. Ifenprodil pretreatment blocked sensitization. c, The morphological response to repeated cocaine exposure was also analyzed; cocaine decreased wild-type oPFC spine density to levels comparable with arg−/− mice, but arg−/− spine density was not sensitive to cocaine. d, Cocaine enlarged remaining wild-type oPFC spine heads, but again, arg−/− spines did not respond to cocaine. e, Overall, wild-type oPFC spine heads were nearly 15% wider after cocaine; arg−/− spines did not change. Symbols and bars represent means + SEMs. *p < 0.05 as indicated.
- Figure 3.
Potentiation of psychostimulant sensitivity by targeted latrunculin A, Abl family kinase inhibition, and p190RhoGAP knockdown. a, Mice were infused into the oPFC with latrunculin A or the Abl family kinase inhibitor STI-571. Both compounds potentiated the locomotor response to five subsequent daily cocaine injections. *p < 0.05 relative to intracranial saline plus systemic saline; #p < 0.05 relative to intracranial saline plus systemic cocaine. b, p190RhoGAP-deficient mice (p190+/−) also showed heightened locomotor sensitivity on par with arg−/− mice, while abl−/− mice did not differ from littermate wild-type mice. *p < 0.05 versus wild type. c, The locomotor response to repeated MPH exposure was also exaggerated in arg−/− mice at a dose matched to cocaine for efficacy at the dopamine transporter (5 mg/kg). *p < 0.05 versus wild type. d, Cocaine- and MPH-induced locomotor hyperactivity in arg−/− and p190+/− mice was persistent, as indicated by increased activity relative to littermate wild-type control mice after a “challenge” injection administered after 7–10 d drug-free. The dashed line at 100% represents the locomotor response to saline. *p < 0.05 versus wild type. The bars and symbols represent group means + SEMs.
- Figure 4.
Arg kinase regulates oPFC-dependent decision making. a, arg−/− mice were impaired in acquiring a new response in an instrumental reversal task. Inset, Responses on the previously reinforced aperture (“inactive” responses) were also exaggerated in arg−/− mice. b, oPFC STI-571 infusions targeted to the lateral compartment selectively impaired response acquisition. c, Impaired acquisition may be attributable to reduced ability to modify behavioral strategies in the presence of reward-predictive stimuli, since arg−/− mice also performed more responses for reward-associated conditioned stimuli (total of 5 test sessions). d, Targeted oPFC STI-571 infusions also increased responding for cues associated with food reinforcement despite equivalent responding for food before infusion. e, Response patterns were unaffected if mice were allowed a 2 week washout period after STI-571 infusion before test. Inset, Representative infusion site at arrow. The symbols represent group means + SEMs. *p < 0.05.
