BACKGROUND: GABA A receptor deficits that are induced by global or forebrain-specific heterozygous inactivation of the γ2 subunit gene in mouse embryos result in behavior indicative of trait anxiety and depressive states. By contrast, a comparable deficit that is delayed to adolescence is without these behavioral consequences. Here we characterized γ2-deficient mice with respect to HPA axis abnormalities and antidepressant drug responses.

Brain-derived neurotrophic factor (BDNF) regulates monoamine neuronal growth, survival and function in development and throughout adulthood. At 18 months of age, mice with constitutive reductions in BDNF expression show decreased serotonin innervation in the hippocampus compared with age-matched wildtype mice. It is not known, however, whether age-accelerated loss of serotonergic innervation in BDNF 1/2 mice occurs in other brain regions, advances beyond 18 months or is associated with alterations in other neurotransmitter systems. In this study, immunocytochemistry was used to assess serotonergic and catecholaminergic innervation in 26-month-old BDNF 1/2 mice. Age-related loss of serotonin axons in the hippocampus was potentiated in BDNF 1/2 mice compared with wildtype mice at this late age, particularly in the CA1 subregion. By contrast, aging BDNF 1/2 mice showed increased serotonin innervation of the basomedial nucleus of the amygdala. In the noradrenergic system, BDNF 1/2 mice showed reduced numbers of cell bodies and fibers in the locus coeruleus compared with age-matched wildtype mice, whereas no changes were observed in dopaminergic innervation with respect to genotype. In vivo zero net flux microdialysis in awake mice showed a significant decrease in extracellular serotonin levels in the hippocampus in BDNF 1/2 mice at 20 months of age. Thus, reduced BDNF is associated with altered serotonergic and noradrenergic innervation in aging mice and, in particular, with accelerated loss of serotonergic innervation to the hippocampus that is manifest as a decrease in basal neurotransmission.

Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2+/− mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2+/− model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2+/− mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2+/− neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2+/− mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2+/− mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.

benzonitrile), recently developed for positron emission tomography (PET) imaging, has been investigated by autoradiography in mice lacking one or both copies of the SERT gene (Li et al., 2004). High densities of [ 3 H]AFM and [ 3 H]DASB binding were observed in the hippocampus, thalamus, raphe nuclei, and locus coeruleus of SERTþ/þ mice. SERTþ/À mice exhibited reduced binding to $50% of that detected in wildtype mice. As anticipated, no binding was observed for either ligand in any of the brain regions analyzed in SERTÀ/À mice (Li et al., 2004). Thus, there is agreement among published studies that intact serotonin transporter protein labeled by many different radioligands is reduced in a gene dose-dependent manner in SERT-deficient mice generated by alternate strategies in a variety of genetic backgrounds. Many studies have been conducted that have assessed the effects of long-term pharmacologic inhibition of serotonin reuptake on SERT protein levels. Here, the majority of studies conclude that a reduction in SERT occurs after chronic administration of selective serotonin reuptake inhibitors (SSRIs) to mice (

1-Methyl-4-(2Ј-aminophenyl)-1,2,3,6-tetrahydropyridine (2Ј-NH 2 -MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its other 2Ј-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2Ј-NH 2 -MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment.To explore the possibility that 5-HT modulates the astrocytic response to injury, 2Ј-NH 2 -MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2Ј-methylphenyl)-1,2,3,6-tetrahydropyridine (2Ј-CH 3 -MPTP). Despite a 90% decrement in striatal DA in 2Ј-NH 2 -MPTP/ 2Ј-CH 3 -MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2Ј-CH 3 -MPTP alone. Thus, 2Ј-NH 2 -MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury.The irreversible Parkinsonian-like syndrome that rapidly developed in a group of Northern California substance abusers in the early 1980s fueled intense investigation of the causative agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model of dopaminergic neurodegeneration. MPTP has since been shown to damage DA neurons of the nigrostriatal pathway in humans (Speciale, 2002) and experimental animals (Heikkila et al., 1984a). As such, MPTP has proven to be an important tool for modeling various aspects of DA degeneration occurring in idiopathic Parkinson's disease (Speciale, 2002).As part of the mechanistic evaluation of MPTP, many analogs were synthesized to elucidate structure-activity relationships (Youngster et al., 1989a;Maret et al., 1990). These studies focused primarily on the ability of MPTPrelated compounds to decrease DA in striatum. In fact, a number of analogs were shown to be at least as potent as MPTP in their ability to deplete DA and many of these possess a substituent at the 2Ј-position (Youngster et al., 1989b). However, a single 2Ј-substituted analog, 1-methyl-4-(2Ј-aminophenyl)-1,2,3,6-tetrahydropyridine (2Ј-NH 2 -MP...