The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals.

Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.

Glucocorticoid receptor mRNA expression in the hippocampal formation of male rats before and after pubertal development in response to acute or repeated stress.

Numerous studies have established that adolescence is marked by substantial changes in stress reactivity and hippocampal function. Glucocorticoid receptors (GRs) in the hippocampus are imperative in corticosterone-dependent gene transcription when glucocorticoid levels are relatively high, such as during periods of stress. As reported previously, in reaction to acute stress, prepubertal animals show a significantly more protracted corticosterone response compared to adults. Chronic stress, however, results in a higher peak response, but a faster return to baseline in prepubertal compared to adult animals. Thus, depending on the developmental stage and experience of the animal, the hippocampus is exposed to different concentrations and durations of corticosterone. The present set of experiments assessed the effects of acute or repeated stress on GR mRNA expression in the dorsal and ventral hippocampal formation either before or after pubertal maturation in male rats. We found that acute stress results in a significant decrease in GR mRNA in the CA1 pyramidal cell layer and dentate gyrus in the dorsal and ventral hippocampal formation of both prepubertal and adult males. In response to repeated stress, we found no differences in GR expression in either the dorsal or ventral hippocampus. Thus, despite the dramatic differences in corticosterone concentration following stress at these two developmental stages, the stress-induced changes in GR expression in the hippocampus before and after pubertal maturation were more similar than different. These data point to a dissociation between differential stress-induced corticosterone responses and regulation of hippocampal GR levels in prepubertal and adult animals.

Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity.

Both the magnitude and the duration of the hormonal stress response change dramatically during neonatal development and aging as well as with prior experience with a stressor. However, surprisingly little is known with regard to how pubertal maturation and experience with stress interact to affect hypothalamic-pituitary-adrenal axis responsiveness. Because adolescence is a period of neurodevelopmental vulnerabilities and opportunities that may be especially sensitive to stress, it is imperative to more fully understand these interactions. Thus, we examined hormonal and neural responses in prepubertal (28 d of age) and adult (77 d of age) male rats after exposure to acute (30 min) or more chronic (30 min/d for 7 d) restraint stress. We report here that after acute stress, prepubertal males exhibited a significantly prolonged hormonal stress response (e.g. ACTH and total and free corticosterone) compared with adults. In contrast, after chronic stress, prepubertal males exhibited a higher response immediately after the stressor, but a faster return to baseline, compared with adults. Additionally, we demonstrate that this differential stress reactivity is associated with differential neuronal activation in the paraventricular nucleus of the hypothalamus, as measured by FOS immunohistochemistry. Using triple-label immunofluorescence histochemistry, we found that a larger proportion of CRH, but not arginine vasopressin, cells are activated in the arginine vasopressin in response to both acute and chronic stress in prepubertal animals compared with adults. These data indicate that experience-dependent plasticity of the hypothalamic-pituitary-adrenal neuroendocrine axis is significantly influenced by pubertal maturation.

Cell-type specific expression of p11 controls cocaine reward.

BACKGROUND: The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10), specifically in the NAc, elicits depressive-like behaviors in mice, but its role in drug addiction is unknown. METHODS: We combined mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (six to eight mice per group) and molecular correlates (three experiments, five to eight mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (five to eight mice per group). RESULTS: We demonstrated that p11 knockout mice have enhanced cocaine conditioned place preference, which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine conditioned place preference. Finally, we identified dopamine receptor-1 expressing medium spiny neurons as key mediators of the effects of p11 on cocaine reward. CONCLUSIONS: Our data provide evidence that disruption of p11 homeostasis in the NAc, particularly in dopamine receptor-1 expressing medium spiny neurons, may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.

Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens.

The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT(1B))] and serotonin 4 (5-HT(4)) receptor-binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)-mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.