Alteration by p11 of mGluR5 localization regulates depression-like behaviors.

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

The role of PKC signaling in CRF-induced modulation of startle.

RATIONALE: Hypersignaling of corticotropin releasing factor (CRF) has been implicated in stress disorders; however, many of its downstream mechanisms of action remain unclear. In vitro, CRF1 receptor activation initiates multiple cell signaling cascades, including protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase kinase MEK1/2 signaling. It is unclear, however, which of these signaling cascades mediate CRF-induced behaviors during stress. OBJECTIVES: We examined the role of PKA, PKC, and MEK1/2 signaling pathways in CRF-induced anxiety as measured by startle hyperreactivity. METHODS: Mice treated with intracerbroventricular (ICV) ovine CRF (oCRF) were pretreated with the PKA inhibitor Rp-cAMPS, PKC inhibitor bisindolylmaleimide (BIM), or MEK1/2 inhibitor PD98059 (ICV) and assessed for acoustic startle reactivity. RESULTS: The PKC inhibitor BIM significantly attenuated CRF-induced increases in startle. BIM was also able to block startle increases induced by oCRF when both compounds were infused directly into the bed nucleus of stria terminalis (BNST). PKA and MEK1/2 inhibition had no significant effects on CRF-induced changes in startle at the dose ranges tested. CRF-induced disruption of prepulse inhibition was not significantly reversed by any of the three pretreatments at the dose ranges tested. CONCLUSIONS: PKC signaling is required for CRF-induced increases in startle, and this effect is mediated at least in part at the BNST. These findings suggest that PKC signaling cascades (1) may be important for the acute effects of CRF to induce startle hyperreactivity and (2) support further research of the role of PKC signaling in startle abnormalities relevant to disorders such as posttraumatic stress disorder.

Sex differences in contextual fear conditioning are associated with differential ventral hippocampal extracellular signal-regulated kinase activation.

Although sex differences have been reported in hippocampal-dependent learning and memory, including contextual fear memories, the underlying molecular mechanisms contributing to such differences are not well understood. The present study examined the extent to which sex differences in contextual fear conditioning are related to differential activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), a protein kinase critically involved in memory formation. We first show that male rats exhibit more long-term retention of contextual fear conditioning than female rats. During a tone test, females spent more time freezing than males, although both sexes exhibited robust retention of auditory fear learning. Using Western blot analysis, we then show that phosphorylated ERK levels in ventral, but not dorsal, hippocampus are higher in males than females, relative to same-sex controls, 60 minutes after fear conditioning. Post-conditioning increases in ERK activation were observed in the amygdala in both males and females, suggesting a selective effect of sex on hippocampal ERK activation. Together, these findings suggest that differential activation of the ERK signal transduction pathway in male and female rats, particularly in the ventral hippocampus, is associated with sex differences in contextual fear.

Environmental enrichment reduces the mnemonic and neural benefits of estrogen.

The degree to which memory is enhanced by estrogen replacement in postmenopausal women may depend on environmental factors such as education. The present study utilized an animal model of environmental enrichment to determine whether environmental factors influence the mnemonic and neural response to estrogen. Female mice were raised in standard (SC) or enriched (EC) conditions from weaning until adulthood (7 months). All mice were ovariectomized at 10 weeks, and tested in object recognition and water-escape motivated radial arm maze (WRAM) tasks at 6 months. Each day at the completion of training, mice received injections of 0.1 mg/kg cyclodextrin-encapsulated 17-beta-estradiol (E2), 0.2 mg/kg E2, or cyclodextrin vehicle (VEH). At the completion of behavioral testing, hippocampal levels of the presynaptic protein synaptophysin and of brain-derived neurotrophic factor (BDNF) were measured. Enrichment effects were evident in VEH-treated mice; relative to SC-VEH females, EC-VEH females committed fewer working memory errors in the WRAM and exhibited increased hippocampal synaptophysin levels. Estrogen effects depended on environmental conditions. E2 (0.2 mg/kg) improved object memory only in SC females. The same dose improved working memory in SC females, but somewhat impaired working memory in EC females. Furthermore, both doses reduced hippocampal synaptophysin levels in EC, but not SC, females. In contrast, E2 reduced hippocampal BDNF levels in SC, but not EC, females. This study is the first to compare the effects of estrogen on memory and hippocampal function in enriched and non-enriched female mice. The results suggest that: (1) estrogen benefits object and working memory more in mice raised in non-enriched environments than in those raised in enriched environments, and (2) the changes induced by estrogen and/or enrichment may be associated with alterations in hippocampal synaptic plasticity.

Schedule-induced polydipsia: gender-specific effects and consequences of prenatal cocaine and postnatal handling.

The impact of gestational cocaine in conjunction with postnatal handling on schedule-induced polydipsia (SIP) was examined. Rat offspring were derived from Sprague-Dawley dams injected subcutaneously with 40 mg/kg/3 cc cocaine hydrochloride (C40) on gestational days 8-20, dams injected with vehicle and pair fed 4 (PF4) days to mimic the acute anorexic effects of cocaine administration, and nontreated (NT) control dams. In adulthood, offspring were food deprived and given 13 daily 30-min SIP sessions, with water intake recorded during the scheduled (fixed time 60 s-FT60) food delivery. For 4 days thereafter, animals received saline, 5 or 10 mg/kg of cocaine in counterbalanced order prior to SIP testing. Acquisition and maintenance of SIP, but not cocaine-induced suppression of SIP performance, were observed to be dependent upon prenatal treatment, handling, and gender. Females acquired SIP faster and exhibited notably higher levels of polydipsia than males. Early handling increased levels of established SIP in NT offspring, while enhancing SIP acquisition in both PF4 and C40 offspring. In nonhandled animals, NT offspring exhibited less SIP than PF4 and C40 offspring, differences that were attenuated by early handling. These effects are discussed in relation to previously reported neurohormonal characteristics of these gender and treatment variables.