Genotypic influences on striatal dopaminergic regulation in mice

Genotypic influences on dopaminergic-induced behaviors and striatal dopaminergic receptors were evaluated in CBA/J, C57BL/6J and BALB/cJ male mice. CBA/J mice were less behaviorally sensitive to apomorphine (stereotypic behavior), but more sensitive to haloperidol (catalepsy) than C57BL/6J and BALB/cJ mice. Striatal dopaminergic receptors, assayed by binding of [³H]spiroperidol (antagonist) and [³H]ADTN (agonist), were 50% fewer in CBA/J compared to BALB/cJ mice; C57BL/6J mice had low to intermediate numbers of receptors.

Striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were similar in all strains. However, a 20% higher DOPAC/dopamine ratio in CBA/J mice suggests greater dopamine turnover. Median eminence dopamine was similar in all strains, but norepinephrine was 30% higher in BALB/cJ mice.

CBA/J mice failed to show antagonist-induced supersensitivity-type responses to chronic haloperidol treatment: enhanced stereotypic response to apomorphine and a 30% increase of dopaminergic receptors occurred in C57BL/6J and BALB/cJ mice, but not in CBA/J mice. These data suggest that CBA/J mice either cannot respond to chronic haloperidol treatment or have an elevated threshold for induction of supersensitivity response.

Chronic treatment with the dopamine agonist bromocriptine (7d) depressed apomorphine-induced stereotypic behavior in C57BL/6J mice and eliminated stereotypy in BALB/cJ mice, but caused no change in stereotypic behavior in CBA/J mice. Dopaminergic receptors were 15% lower after bromocriptine treatment in all strains.

These results suggest that some striatal dopaminergic functions are impaired in CBA/J mice relative to BALB/cJ and C57BL/6J mice. The impaired haloperidol-induced supersensitivity responses in the CBA/J mouse may be a useful model for analyzing similar impairments of supersensitivity responses in old rodents.     

Genotypic variation in striatal calmodulin content

CBA/J and BALB/cJ mice have quantitative differences in the nigrostriatal projection. The number of nigral tyrosine hydroxylase reactive neurons, nigral and striatal tyrosine hydroxylase activity and the density of striatal D-2 dopamine receptors are all less in the CBA/J compared to the BALB/cJ mouse. An unrelated strain, the C57BL/6J, has a striatal D-2 dopamine receptor density that is intermediate to that of CBA/J and BALB/cJ mice. CBA/J mice also show deficits in the ability of brain monoaminergic receptor systems to develop supersensitivity. Calmodulin may participate in several striatal dopaminergic receptor mechanisms. Thus, striatal calmodulin was examined in CBA/J, C57BL/6J and BALB/cJ mice. Striatal calmodulin was greater in CBA/J mice than in C57BL/6J or BALB/cJ. In all three strains, cerebral cortical calmodulin was similar. The percent distribution of total striatal calmodulin between soluble and particulate fractions was similar in the three strains. Calcium redistributed soluble striatal calmodulin into the particulate fraction and EGTA shifted calmodulin from the particulate into the soluble fraction. The percent of total striatal calmodulin redistributed by either treatment was similar in all three strains. Gel filtration chromatography of heat-treated soluble extracts from CBA/J and BALB/cJ striatum was similar in elution pattern, although more calmodulin was observed in extracts from the CBA/J. Possible mechanisms for the strain differences in calmodulin are discussed along with their relationship to strain differences in striatal dopamine receptor subtypes.     

Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra

Immune/inflammatory factors have been implicated in the pathogenesis of Parkinson's disease (PD). Immunoglobulin G (IgG) from patients with PD can induce injury of dopaminergic neurons following stereotaxic injection into rat substantia nigra (SN). The PD IgG can be demonstrated in vitro to activate microglia via the Fcgamma receptor (Fcgamma R) and induce dopaminergic cell injury. To confirm the involvement of microglia and their Fcgamma R in IgG-induced lesions of SN in vivo we analyzed the tyrosine hydroxylase (TH)-positive cell loss in SN par compacta (SNpc) in mice lacking Fcgamma receptors (Fcgamma R(-/-)) and wild type (Fcgamma R(+/+)). At 1 day after stereotaxic injection of PD IgG into the SN of Fcgamma R(+/+) mice there was a 27% increase in the number of CD11b-positive microglial cells and no significant loss of TH-positive cells. At 14 days after the stereotaxic injection, the number of microglial cells was increased by 42%, accompanied by a 40% loss of TH-positive neurons in the SNpc. PD IgG injection in Fcgamma R(-/-) mice resulted in no significant increase of microglia and no loss of TH-positive cells in the SNpc at any time point. The injection of F(ab')(2) fragments of PD IgG was able to induce TH-positive neuronal loss in the SNpc only when the injected animals raised antibodies against the injected human IgG fragments, which confirmed the importance of the Fcgamma R in microglial activation and nigral injury.     

Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains

We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL/6, ICR, FVB/N, and BALB/c strains were resistant to seizures while the C57BL/10, DBA/2 J, and F1 C57BL/6*CBA/J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL/6, C57BL/10, and F1 C57BL/6*CBA/J strains were resistant to neurodegeneration while the FVB/N, ICR and DBA/2 J strains were vulnerable. The BALB/c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.     

Neurospecific S-100 protein content in brains of different mouse strains

Total whole brain concentrations of S-100 protein and of its water-soluble fraction were determined in 11 inbred mouse straine: DBA/2J, AKR/J, CBA/Lac, C57BL/6J, C57BL/6J-Ay, C3H/He, C3H/f, DD, A/He, BALB/cLac, CC57BR/Mv, and in cerebral cortex, cerebellum and hippocampus in DBA/2J, AKR/J and CBA/Lac strains. Highly significant differences in the concentrations of the water-soluble S-100 protein were found between some strains. Slight differences were found in total S-100 protein content in whole brains between the strains (0.01 less that P less than 0.05). The DBA/2J mice had the highest brain S-100 protein content, and were characterized by a higher learning rate in shuttle-box as compared to CBA/Lac and AKR/J mice, who had a low content of this neurospecific protein.     

Increased chemokine gene expression during aging in the murine brain

Normal aging results in changes in the brain that contribute to the decline of various functions, including learning and memory. Mechanisms causing this decline have not been clearly established. Activation of microglia is associated with the normal aging process in rodents and primates. Microglial activation is regulated by chemokine gene expression, and activated microglia produce substances that can be detrimental to surrounding cells. In this study we determined whether changes in chemokine expression occur during normal aging in the mouse brain. RNA samples taken from the cortex, midbrain, hippocampus, and cerebellum of 4-, 10-, 21- and 30-month-old C57BL6/DBA2 mice were analyzed for changes in gene expression. RNase protection assays were used to examine a panel of chemokines. Increased expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES occurred in all four regions of the brains in the oldest mice. These increases were first detectable at 21 months of age. Increases in MIP-1alpha, MIP-1beta, and RANTES protein levels were also detected in the brains of old mice, as measured by ELISA. Increased microglial activation in the brains of 30-month-old mice, as detected by immunohistochemistry using F4/80 antibodies, correlated with increases in chemokine expression. The observed increases in chemokine gene expression that occur in conjunction with increased microglial activation suggest that chemokines may contribute to the decreased brain function that occurs during normal aging.     

Proteomic analysis of microglial contribution to mouse strain-dependent dopaminergic neurotoxicity

Although the pathogenesis of Parkinson's disease (PD) remains unknown, it appears that microglial activation is associated with enhanced neurodegeneration in animal models of PD as well as in PD patients. Experimentally, C57BL/6 and SWR/J mice demonstrate striking differences in the extent of dopaminergic (DAergic) neurodegeneration induced by a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The purpose of this study was to determine whether differences in microglial activation between these two strains of mice could provide insight into the variability seen in toxicant induced neuronal death, and subsequently to use a high-throughput proteomic method, combining stable isotope labeling with amino acids in cell culture (SILAC) with liquid chromatography and tandem mass spectrometry, to compare the microglial proteomes of C57BL/6 and SWR/J mice after stimulation with a classical microglial activator, lipopolysaccharide (LPS). We found that DAergic neurotoxicity induced by LPS in a primary neuron-microglia coculture was twofold greater with microglia isolated from the brains of C57BL/6 mice compared with that of SWR/J mice. Upon proteomic analysis we found that, out of over 1,000 proteins identified and quantified, 400 displayed a significant difference in their relative abundance between these two murine strains. Several proteins, which had relatively higher levels in C57BL/6 mice, have previously been implicated in LPS-mediated microglial activation, including those involved in the COX-2 pathway and in prostaglandin E-2 (PGE(2)) production. To validate our proteomic results we confirmed the increased expression level of iNOS in C57BL/6 vs. SWR/J microglia with semiquantitative Western blot. Further analysis of our proteomic discovery data will likely reveal numerous novel proteins involved in inflammation-mediated neurotoxicity in PD.     

Modeling Alzheimer's disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide

The induction of an antibody response to amyloid beta (Abeta) peptide has become a strategy for the treatment of Alzheimer's disease (AD). This has proven effective in reducing the plaque burden in transgenic mice that develop Abeta plaques similar to human AD patients. The mechanism for enhanced clearance of Abeta is partly due to the interaction of immunoglobulin Fcgamma receptor-expressing microglia and specific antibody-opsonized Abeta deposits. This interaction can stimulate Fcgamma receptor-mediated phagocytosis, but also results in inflammatory activation of these cells. Consequently, interaction of microglia with antibody-antigen complexes could exacerbate the existing inflammation in the brains of AD patients. In this study, we used substrate-bound Abeta and cultured human microglia from AD and non-demented cases to model interaction of microglia and antibody-opsonized plaques in AD brains. Enhanced production of tumor necrosis factor-alpha, macrophage colony stimulating factor, interleukin-10, and superoxide ions was detected. We also demonstrated enhanced uptake of opsonized Abeta by microglia, which was reduced significantly in the presence of excess IgG, indicative of the involvement of Fcgamma receptor-mediated mechanisms. Human microglia were shown in this study to express mRNA for Fcgamma receptors I, IIa, IIb, and III. The expression of Fcgamma receptor II was augmented by proinflammatory stimulation. These results suggest that initial interactions of human microglia with antibody-opsonized amyloid could result in increased inflammation. The consequence of this on inflammatory pathology in AD brains needs to be considered before immunization is used as a strategy for treating AD.     

MHC class II-positive perivascular microglial cells mediate resistance to Cryptococcus neoformans brain infection

Acquired resistance to the CNS pathogen Cryptococcus neoformans is mediated by CD4(+) T lymphocytes primed by exposure to antigen in the context of major histocompatibility class II (MHC II) molecules. In mouse brain, parenchymal and perivascular microglial cells may express interferon-gamma (IFN-gamma)-inducible MHC class II marker and thus interact with CD4(+) T cells. Primed effector T cells are retained in the infected CNS if antigen is encountered in proper MHC context and may deliver signals that potentiate microglia to enhanced fungistasis. Vaccinated C57BL6/J mice resist an ordinarily lethal C. neoformans rechallenge, but identically treated congenic Abeta(o/o) mice (MHC class II-deficient; CD4(+) T-cell-deficient) do not. Nor can Abeta(o/o) mice be adoptively immunized by infusion of lymphocytes from vaccinated C57BL6/J donors, as are severe combined immunodeficient (SCID) mice (MHC class II-intact, lymphocyte-deficient). Chimeric (C57BL/6J:Abeta(o/o)) mice with class II expression likely on perivascular microglia only were, like SCID mice, capable of adoptive immunization against C. neoformans brain infection. To the contrary, chimeric mice with class II expression likely only on parenchymal microglia were not capable of effective adoptive immunization against C. neoformans brain infection. Therefore, in order to mediate resistance to infection, primed CD4(+) T cells must interact with the replenishable perivascular microglial subset that lies in close proximity to cerebral vasculature. Although T cells may supply help in the form of inflammatory cytokines to parenchymal microglia, expression of class II on these cells appears unnecessary for antifungal activity.     

Immunochemical studies of brain glutamate decarboxylase and GABA-transaminase of six inbred strains of mice

Six different inbred strains of mice (C57BL/6J, CBA/CaJ, CE/J, DBA/2J, LP/J and RF/J) were compared in terms of specific activities and immunochemical properties of brain L-glutamate decarboxylase (GAD) and gamma-aminobutyrate transaminase (GABA-T), the enzymes responsible for the synthesis and degradation of GABA, respectively. GAD from the brains of the different strains was indistinguishable on the basis of specific activities, double diffusion tests, immunoelectrophoresis and inhibition by antibody. However, microcomplement fixation tests showed GAD from DBA and C57BL mice to be most distinctly different from GAD extracted from the Swiss mouse, from which the original antigen was prepared and that the enzyme from the CE, LP and RF also differed. Similar fixation curves were obtained for the GAD from CBA and Swiss mice. GABA-T from the different strains was indistinguishable on the basis of all the tests employed.     

In vivo and in vitro glycogenic effects of methionine sulfoximine are different in two inbred strains of mice

We investigated the relationship between brain glycogen anabolism and methionine sulfoximine (MSO)-induced seizures in two inbred mouse strains that presented differential susceptibility to the convulsant. CBA/J was considered a MSO-high-reactive strain and C57BL/6J a MSO-low-reactive strain. Accordingly, the dose of MSO needed to induce seizures in CBA/J mice is lower than that in C57BL/6J mice, and CBA/J mice which had seizures, died during the first convulsion. In addition, the time--course of the MSO effect is faster in CBA/J mice than that in C57BL/6J mice. Analyses were performed in C57BL/6J and CBA/J mice after administration of 75 (subconvulsive dose) and 40 mg/kg of MSO (subconvulsive dose, not lethal dose), respectively. In the preconvulsive period, MSO induced an increase in the brain glycogen content of C57BL/6J mice only. Twenty-four hours after MSO administration, the brain glycogen content increased in both strains. The activity and expression of fructose-1,6-bisphosphatase, the last key enzyme of the gluconeogenic pathway, were increased in MSO-treated C57BL/6J mice as compared to control mice, at all experimental time points, whereas they were increased in CBA/J mice only 24 h after MSO administration. These latter results correspond to CBA/J mice that did not have seizures. Interestingly, the differences observed in vivo were consistent with results in primary cultured astrocytes from the two strains. This data suggests that the metabolism impairment, which was not a consequence of seizures, could be related to the difference in seizure susceptibility between the two strains, depending on their genetic background.     

Neuronal and astrocyte expression of nicotinic receptor subunit beta4 in the adult mouse brain

Neuronal nicotinic acetylcholine receptor (nAChR) expression and function are customized in different brain regions through assembling receptors from closely related but genetically distinct subunits. Immunohistochemical analysis of one of these subunits, nAChRbeta4, in the mouse brain suggests an extensive and potentially diverse role for this subunit in both excitatory and inhibitory neurotransmission. Prominent immunostaining included: 1) the medial habenula, efferents composing the fasciculus retroflexus, and the interpeduncular nucleus; 2) nuclei and ascending tracts of the auditory system inclusive of the medial geniculate; 3) the sensory cortex barrel field and cell bodies of the ventral thalamic nucleus; 4) olfactory-associated structures and the piriform cortex; and 5) sensory and motor trigeminal nuclei. In the hippocampus, nAChRbeta4 staining was limited to dendrites and soma of a subset of glutamic acid dehydrogenase-positive neurons. In C57BL/6 mice, but to a lesser extent in C3H/J, CBA/J, or CF1 mice, a subpopulation of astrocytes in the hippocampal CA1 region prominently expressed nAChRbeta4 (and nAChRalpha4). Collectively, these results suggest that the unique functional and pharmacological properties exerted by nAChRbeta4 on nAChR function could modify and specialize the development of strain-specific sensory and hippocampal-related characteristics of nicotine sensitivity including the development of tolerance.     

Differences in the amyloid-beta-induced inflammatory response in microglia from C57BL/6 and A/J strains of mice

The microglial inflammatory response to Abeta(1-42) stimulation with or without IFN-gamma priming was investigated in low and high responder strains of mice, A/J and C57BL/6, respectively. A/J microglia showed moderate morphological changes upon stimulation with IFN-gamma alone or with Abeta(1-42). Conversely, C57BL/6 microglia showed major changes in their cellular morphology, which were accompanied by a decrease in NO release and a marked increase in TNF-alpha production. These results indicate that the magnitude of the microglial inflammatory response to Abeta is strongly influenced by genetic factors. Individual differences in the regulation of the microglial response may be a key player in the rate of development of the neuropathology of AD.     

Genotypic influences on pituitary responsiveness to haloperidol in mice

Previous studies from this laboratory demonstrated that CBA/J mice have impaired striatal dopaminergic supersensitivity in response to subchronic haloperidol administration. Others have speculated that the peripheral hyperprolactinemia produced by haloperidol is necessary for the striatal dopamine receptor supersensitization produced by dopamine antagonists. In the present experiments, we tested the hypothesis that the impaired supersensitization response to haloperidol in CBA/J mice was secondary to an impaired hyperprolactinemic response by comparing the CBA/J mice with other mice that show normal supersensitization responses: the BALB/cJ and C57BL/6J strains. Acute haloperidol treatments increased serum prolactin levels 60 min later in all three strains, with the greatest response in CBA/J mice. After longer haloperidol treatment (2 or 21 days), serum prolactin remained elevated in CBA/J and, to a lesser extent, in C57BL/6J mice; levels remained low throughout treatment in BALB/cJ mice. Although, the basal density of pituitary dopamine receptors [( 3H]spiperone or D-2 binding sites) was greater in CBA/J than BALB/cJ mice, only BALB/cJ mice showed increased pituitary D-2 binding sites following chronic haloperidol administration. Taken together with previous studies of dopamine and noradrenaline receptors in these mouse strains, we conclude that CBA/J mice have a generalized impairment in their supersensitization responses to pharmacologic blockade of receptors. These data do not support the involvement of prolactin in haloperidol-induced dopamine receptor up-regulation.     

Age-related gliosis in the white matter of mice

A histopathologic study of the brains from 96 mice, ranging in age from 3 to 57 months in age, documents an age-associated increase in hupertrophic astrocytes in white matter. This report of gliosis is distinct from previously reported proliferation of glial cells in the grey matter. Four genotypes, CBA/HT6J, C57BL/6J, B6CBAT6F₁J, and B6C3F₁ were positive for this age-related lesion. Most very old mice utilized in this study were calorically restricted, a dietary manipulation long known to result in increased longevity in rodents. Caloric restriction appears to delay the age associated increase of this lesion. Immunoperoxidase staining for the astrocycte-specific glial fibrillary acidic protein (GFAP) confirmed the progressive increase in the density of stainable astrocytes with increase in age. GFAP staining of white matter increased in both diet groups with age. These findings present an interesting model for the study of aberrant cellular activity and perhaps neurodegeneration, modulated by caloric restriction.     

Neurobehavioral Effects of Anandamide and Cannabinoid Receptor Gene Expression in Mice

The objective of the present study was to determine the neurobehavioral effects of the putative endogenous cannabinoid ligand, anandamide, and its influence on cannabinoid (CB₁) receptor gene expression. The effect of acute administration of anandamide to C57BL/6, DBA/2, and ICR mice were evaluated in motor function and emotionality tests. The C57BL/6 and ICR mouse strains were more sensitive than the DBA/2 strain to the depression of locomotor activity and stereotyped behavior caused by anandamide. Although anandamide produced catalepsy in all three strains, anandamide induced ataxia in the minus-maze test only in the C57BL/6 animals and only at the lowest dose used. In the plus-maze test system, anandamide produced a mild aversive response, and by the third day of treatment the mouse strains developed an intense aversion to the open arms of the plus-maze. Northern analysis data using the recently cloned mouse cannabinoid receptor cDNA as a probe indicated that there was abundant expression of CB₁ gene in the whole brain of the ICR mouse than in the brains of the C57BL/6 and DBA/2 strains with or without pretreatment with anandamide. The anandamide induced neurobehavioral profile does not seem to correspond to the CB₁ gene expression in the mouse strains. It is, therefore, unlikely that the CB1 receptor mediates all the cannabinomimetic effects of anandamide in the brain.     

Sex difference and laterality in the volume of mouse dentate gyrus granule cell layer

Sex differences in spatial learning have been reported in both humans and rodents. Correspondingly, there have been reports of sexual dimorphism in the morphology of the hippocampal formation (HF), a brain structure implicated in spatial cognition. In Experiment 1, we confirmed earlier reports that the overall volume of the granule cell layer (GCL) of the dentate gyrus (DG) of A/J mice is larger in males than in females. We also found that male A/J mice have a larger GCL volume in the right hemisphere than the left. Female A/J mice displayed no such laterality. A similar pattern of laterality, favoring the right HF, had been reported previously in male, but not female, rats. In Experiment 2, we examined mice with a defective structural gene for androgen receptors (testicular feminization mutant, or tfm mice) on a C57/BL6J background. The C57/J strain had not previously been examined for hippocampal sexual dimorphism. We found no sexual dimorphism in the left, right, or total volume of the GCL in C57/BL6J mice whether they were wildtype or tfm. However, the right GCL volume was greater than the left in wildtype C57/BL6J mice of either sex. No lateralization of GCL volume was found in the androgen-insensitive tfm-affected males or the partially androgen-insensitive tfm-carrier females. These findings confirm earlier reports that sexual dimorphism in mouse HF is found in some inbred strains but not others, and indicate for the first time that mouse HF structures are lateralized. The absence of lateralization in partially or wholly androgen-insensitive mice suggests that androgen receptors may play a role in development of laterality in the GCL independently of any sexual dimorphism in this structure.     

Microglia demonstrate age-dependent interaction with amyloid-β fibrils

Alzheimer's disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-β (Aβ) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar Aβ1-42 in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with Aβ fibrils. In order to better define a temporal profile of microglia-Aβ interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared. Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose Aβ fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease Aβ immunoreactive plaque load from AD sections in vitro. In spite of limited Aβ uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both Aβ plaques and in vitro fibrillized Aβ. These data demonstrate a temporal profile of specifically Aβ-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with Aβ fibrils but lose their ability to phagocytose it.     

Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer’s disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral β-amyloid (Aβ) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased Aβ accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD.     

Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal

Etiopathogenesis of depression and the cause of insensitivity to treatment remain poorly understood, although genetic makeup has been established as a contributing factor. The isogenicity of inbred mouse strains provides a useful tool for investigating the link between genes and behavior or drug response. Hence, our aim was to identify inbred mouse strains (among A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) sensitive to a 9-week period of unpredictable chronic mild stress (UCMS) and, from the fifth week onward, to the reversal effect of an antidepressant (AD) (imipramine, 20 mg/kg/day i.p.) on various depression-related changes: physical, behavioral and neuroendocrine states. UCMS induced a significant deterioration of the coat state (in all the strains), blunted emotional reactivity in the novelty-suppressed feeding (NSF) test (A/J, BALB/c, C57BL/6), and changes in the level of fecal corticosterone metabolites (BALB/c, C57BL/6, DBA, FVB). Imipramine treatment reversed the UCMS-induced alterations of the coat state (BALB/c, DBA), in the NSF test (A/J, BALB/c, C57BL/6) and in fecal corticosterone metabolites (BALB/c, C57BL/6). C3H, CBA and FVB mice were irresponsive to imipramine treatment. It is noteworthy that UCMS-induced physical or behavioral changes occurred without hypothalamo–pituitary–adrenal (HPA) axis alterations in some strains (A/J, C3H, CBA), although the AD-induced reversal of these changes in BALB/c and C57BL/6 was associated with HPA axis normalization. Finally, UCMS is shown to discriminate various alterations and to replicate in a strain-dependent manner diverse profiles reminiscent of human disease subtypes. UCMS may thus enable the selection of strains suitable for investigating specific depression-related features and could be an appropriate model for identifying genetic factors associated with increased vulnerability, specific symptoms of affective disorders, and AD resistance.