Chronic SSRI Treatment, but Not Norepinephrine Reuptake Inhibitor Treatment, Increases Neurogenesis in Juvenile Rats.

There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use of antidepressant drugs in adolescents; however, not all classes of antidepressants are effective in children and adolescents. There is an increasing need to understand the differences in antidepressant action in different developmental stages. There are some data indicating that the behavioral effect of chronic antidepressant treatment in adult rodents is dependent on hippocampal neurogenesis; however, it is not known which classes of antidepressant drugs induce hippocampal neurogenesis in adolescent rodents. Three classes of antidepressant drugs were tested in two age groups of Sprague Dawley rats, pre-adolescent (postnatal days 11-24) and adolescent (postnatal days 21-34): monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); and tricyclic antidepressants (TCAs). To address which classes of antidepressant drugs might alter the rate of mitogenesis in neural progenitor cells in an adolescent rodent model, adolescent Sprague Dawley rats were treated with the thymidine analog 5-bromo-deoxy-2'-uridine (BrdU) on postnatal days 21 and 22 and antidepressant drugs or vehicle for 14 days (postnatal days 21-34). To address which classes of antidepressant drugs might alter the rate of neurogenesis, postnatal day-21 Sprague Dawley rats were treated with antidepressant drugs or vehicle for 14 days (postnatal days 21-34) and BrdU on postnatal days 33 and 34. In both experimental paradigms, BrdU-positive cells in the subgranular zone and the granule cell layer were counted. Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11-24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known.

Corticosterone Induces Depressive-Like Behavior in Female Peri-Pubescent Rats, but Not in Pre-Pubescent Rats.

BACKGROUND: There are no data on the effect of exogenous corticosterone on depressive-like behavior in juvenile rats. Furthermore, it has not been tested whether the effects of corticosterone in female rats is different before or after puberty. OBJECTIVE: We tested the effect of corticosterone treatment on female pre- and peri-pubescent juvenile rats on depressive-like behavior. METHODS: Female juvenile rats were divided into pre-pubescent (post-natal day 7-27) or peri-pubescent (post-natal day 28-48) groups and administered daily corticosterone (40 mg kg-1 day-1) for 21 days. Depressive-like behavior was assessed using a modified forced swim test and the sucrose preference test. After behavioral assessment, brains were analyzed to determine if there were changes in cell proliferation and newborn neuron survival in the dentate gyrus of the dorsal hippocampus. RESULTS: Chronic corticosterone treatment did not affect behavior or neurogenesis in female pre-pubescent juvenile rats. However, female peri-pubescent rats injected with corticosterone showed increased depressive-like behavior as well as a decrease in cell proliferation in the subgranular zone. Furthermore, there was an inverse correlation between time spent immobile in the forced swim test and cell proliferation in the granule cell layer in peri-pubescent rats. CONCLUSIONS: Corticosterone induces depressive-like behavior in peri-pubescent, but not in pre-pubescent female rats. Finally, our results suggest that depressive-like behavior may be associated with a decrease in hippocampal cell proliferation in female peri-pubescent rats.

Intracerebroventricular Ghrelin Administration Increases Depressive-Like Behavior in Male Juvenile Rats.

Major depressive disorder (MDD) is arguably the largest contributor to the global disease and disability burden, but very few treatment options exist for juvenile MDD patients. Ghrelin is the principal hunger-stimulating peptide, and it has also been shown to reduce depressive-like symptoms in adult rodents. We examined the effects of intracerebroventricular (icv) injection of ghrelin on depressive-like behavior. Moreover, we determined whether ghrelin increased neurogenesis in the hippocampus. Ghrelin (0.2-nM, 0.5-nM, and 1.0-nM) was administered acutely by icv injection to juvenile rats to determine the most effective dose (0.5-nM) by a validated feeding behavior test and using the forced swim test (FST) as an indicator of depressive-like behavior. 0.5-nM ghrelin was then administered icv against an artificial cerebrospinal fluid (aCSF) vehicle control to determine behavioral changes in the tail suspension test (TST) as an indicator of depressive-like behavior. Neurogenesis was investigated using a mitogenic paradigm, as well as a neurogenic paradigm to assess whether ghrelin altered neurogenesis. Newborn hippocampal cells were marked using 5'-bromo-2'-deoxyuridine (BrdU) administered intraperitoneally (ip) at either the end or the beginning of the experiment for the mitogenic and neurogenic paradigms, respectively. We found that ghrelin administration increased immobility time in the TST. Treatment with ghrelin did not change mitogenesis or neurogenesis. These results suggest that ghrelin administration does not have an antidepressant effect in juvenile rats. In contrast to adult rodents, ghrelin increases depressive-like behavior in male juvenile rats. These results highlight the need to better delineate differences in the neuropharmacology of depressive-like behavior between juvenile and adult rodents.

The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) and other neurotrophins induce a unique prolonged activation of mitogen-activated protein kinase (MAPK) compared with growth factors. Characterization and kinetic and spatial modeling of the signaling pathways underlying this prolonged MAPK activation by BDNF will be important in understanding the physiological role of BDNF in many complex systems in the nervous system. In addition to Shc, fibroblast growth factor receptor substrate 2 (FRS2) is required for the BDNF-induced activation of MAPK. BDNF induces phosphorylation of FRS2. However, BDNF does not induce phosphorylation of FRS2 in cells expressing a deletion mutant of TrkB (TrkBDeltaPTB) missing the juxtamembrane NPXY motif. This motif is the binding site for SHC. NPXY is the consensus sequence for phosphotyrosine binding (PTB) domains, and notably, FRS2 and SHC contain PTB domains. This NPXY motif, which contains tyrosine 484 of TrkB, is therefore the binding site for both FRS2 and SHC. Moreover, the proline containing region (VIENP) of the NPXY motif is also required for FRS2 and SHC phosphorylation, which indicates this region is an important component of FRS2 and SHC recognition by TrkB. Previously, we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 (Grb2). Now, we have intriguing data that indicates BDNF induces association of the SH2 domain containing protein tyrosine phosphatase, Shp2, with FRS2. Moreover, the PTB association motif of TrkB containing tyrosine 484 is required for the BDNF-induced association of Shp2 with FRS2 and the phosphorylation of Shp2. These results imply that FRS2 and Shp2 are in a BDNF signaling pathway. Shp2 is required for complete MAPK activation by BDNF, as expression of a dominant negative Shp2 in cells attenuates BDNF-induced activation of MAPK. Moreover, expression of a dominant negative Shp2 attenuates Ras activation showing that the protein tyrosine phosphatase is required for complete activation of MAPKs by BDNF. In conclusion, Shp2 regulates BDNF signaling through the MAPK pathway by regulating either Ras directly or alternatively, by signaling components upstream of Ras. Characterization of MAPK signaling controlled by BDNF is likely to be required to understand the complex physiological role of BDNF in neuronal systems ranging from the regulation of neuronal growth and survival to the regulation of synapses.