Differential susceptibility to striatal neurodegeneration induced by quinolinic acid and kainate in inbred, outbred and hybrid mouse strains

In mice, the genetic background determines susceptibility to hippocampal neurodegeneration induced by the excitotoxin kainic acid (KA). If genetic background plays as significant a role in the striatum, the area most affected in Huntington's disease (HD), it is important to characterize intrinsic differences in neuronal susceptibility in mouse strains used in HD models. This study was performed to investigate whether strain differences of different HD mouse models are determinants of striatal resistance to excitotoxicity. We conducted a survey of the susceptibility of striatal neurons to neurodegeneration induced by quinolinic acid and KA in six inbred, two outbred and two F1 hybrid (resistant*vulnerable) strains. These are the same strains in which we have assessed vulnerability to KA-induced hippocampal neurodegeneration. We found significant strain differences in response to both excitotoxins and, for the most part, the strain-dependent patterns of susceptibility to quinolinic acid and KA were similar and comparable to those previously found with KA-induced hippocampal neurodegeneration. There were some incongruities, suggesting that the genetic determinants may be different for the two forms of excitotoxicity or that there are important interacting factors. For example, the F1 hybrid strains exhibited neurodegeneration similar to their vulnerable parent, indicating that the vulnerable phenotype is dominant. This is in contrast to KA-induced hippocampal neurodegeneration, where F1 hybrids exhibit the resistant phenotype. These results are also of significance with regard to the issue of region-specific vulnerability in the context of different diseases in which genetic modifiers affect age of onset and/or disease progression.     

Genetic control of apomorphine-induced climbing behavior in two inbred mouse strains

Over a wide dose range (1–32 mg/kg), apomorphine-induced climbing behavior was significantly greater in the AKR/J than in the DBA/2J inbred mouse strain. A similar difference was found when apomorphine-induced stereotypy was examined. A cross-fostering study demonstrated that the strain difference in apomorphine-induced climbing behavior did not result from differences in post-natal rearing environment. After apomorphine administration, brain levels of the drug were similar in the two strains indicating that the difference in behavioral response to apomorphine in the two strains was not due to differences in metabolism or distribution of the drug. The climbing response to apomorphine was examined in the F1 cross of the two strains (AKD2F1/J) and in 10 AKXD recombinant inbred strains. Results suggested that the trait was partially dominant and not X-linked; furthermore, a few and possibly one locus was responsible for the differences in apomorphine-induced climbing behavior observed in the AKR/J and DBA/2J mice.     

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.     

Differential sensitivity to bicuculline in three inbred mouse strains

We examined the inbred mouse strains DBA/2Ibg, C57BL/6Ibg, and C3H/2Ibg for differences in susceptibility to bicuculline-induced seizures, as well as to bicuculline-induced epileptiform activity recorded in the CA1 pyramidal cell layer of hippocampal slices. For susceptibility to seizure onset the strain rank order was (most to least susceptible): C3H = DBA greater than C57. The rank order for sensitivity to effects of bicuculline on tonic seizure latency and on hippocampal epileptiform activity were identical: C3H greater than DBA = C57. It is suggested that mechanisms underlying the development of bicuculline-induced epileptiform events in the hippocampal slice may be similar to those involved in the development of tonic seizures measured in vivo.     

Genetic brain polypeptide variants in inbred mice and in mouse strains with high and low sensitivity to alcohol

Twelve genetically determined brain polypeptide charge variants were identified by comparing cerebellar vermis of 7 inbred mouse strains and of mice selectively bred from 8 strains closely related to these 7 ancestral strains and one other for acute behavioral sensitivity to the sedative effects of ethanol. The selectively bred ethanol-sensitive (LS, long sleep) and insensitive (SS, short sleep) mice exhibited different allelic variants at 6 of these 12 gene loci expressed in the cerebellum. Variant polypeptide A1 (81 kdalton, pI 5.6) was shown to be associated with the membrane of synaptosomal mitochondria and to exhibit a basic variant in SS mice that is determined by a dominant allele. Other variant polypeptides showed codominant inheritance in F1 crosses. However, the phenotype of no single one of these brain polypeptides consistently correlated with the ethanol behavioral sensitivity of the 7 inbred mouse strains nor of 8 recombinant inbred (B X D, C57BL X DBA) strains. This finding supports the hypothesis that a substantial amount of inbreeding, leading to random fixation of alleles independent of selection for ethanol sensitivity, occurred during the breeding of the SS and LS mice. The present findings of a lack of a strong association between sleep time and a brain polypeptide variant do not preclude the existence of a major gene effect contributing to variation in acute sensitivity to ethanol but are consistent with reports that multiple loci are responsible for the difference in ethanol sensitivity between SS and LS mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic diversity underlying capsaicin intake in the Mishima battery of mouse strains

Capsaicin is the active substance responsible for the pungent sensation produced by red pepper. In order to approach the underlying genetic mechanism for preference of red pepper, we conducted a 12-h, 1-bottle intake test of capsaicin solution using both male and female animals from the Mishima battery of mouse strains: 10 wild-derived inbred strains (PGN2, BFM/2, HMI, CAST/Ei, NJL, BLG2, CHD, SWN, KJR, MSM), 1 strain derived from the so-called fancy mouse (JF1), and 3 widely used laboratory strains (C57BL/6J, DBA/1J and BALB/cAnN). The concentration of capsaicin was increased from 0.5 to 15 microM successively. Gender differences were not observed in this test, but we found striking strain differences in capsaicin intake. Relative to baseline water intake, C57BL/6J and DBA/1J consumed 10%, whereas two wild strains, KJR and MSM, ingested approximately 60% of the 15-microM capsaicin solution. In a 2-bottle fluid preference test, both C57BL/6J and MSM strains reject capsaicin fluid even at the 0.5-microM concentration, which indicates that the receptors for capsaicin in these strains recognize capsaicin at a similar level. Thus, the strain differences at higher capsaicin concentrations in the 1-bottle test may reflect differences in central nervous system response to the capsaicin solution. The genetic difference in intake of capsaicin observed in these strains may provide a useful tool for identifying genes underlying response to red pepper in mice and other mammalian species.     

Spinal leptomeningeal epidermoid cysts in inbred mouse strains

Summary The anatomic location and histological appearance of spinal cord epidermoid cysts in a variety of inbred mouse strains was examined. A variable incidence of cysts was found in mice of the C57BR/cdJ, C57BL/6J, B10.BR/SgSnJ, C58/J, AKR/J, C57L/J, and RF/J strains. Cysts were largely found in the leptomeninges, adjacent to the posterior horn and the lateral or anterior columns. The cysts consisted of a central whorled mass of keratinized cells surrounded by polygonal epithelial cells; some of these cells contained keratohyaline granules. Basal cells were absent. The presence of cysts did not correlate with the H-2^k or H-2^b haplotypes of the mouse.Supported by the Medical Research Service of the Veterans Administration Medical Center, Salt Lake City, Utah, by Public Health Service Grant NS11036 from the National Institutes of Neurological and Communicative Disorders and Stroke (NINCDS), and by National Research Service award NS0718002 in neurovirology and microbiology from the NINCDS     

Social approach and repetitive behavior in eleven inbred mouse strains

Core symptoms of autism include deficits in social interaction, impaired communication, and restricted, repetitive behaviors. The repetitive behavior domain encompasses abnormal motoric stereotypy, an inflexible insistence on sameness, and resistance to change. In recent years, many genetic mouse models of autism and related disorders have been developed, based on candidate genes for disease susceptibility. The present studies are part of an ongoing initiative to develop appropriate behavioral tasks for the evaluation of mouse models relevant to autism. We have previously reported profiles for sociability, preference for social novelty, and resistance to changes in a learned pattern of behavior, as well as other functional domains, for 10 inbred mouse strains of divergent genetic backgrounds. The present studies extend this multi-component behavioral characterization to several additional strains: C58/J, NOD/LtJ, NZB/B1NJ, PL/J, SJL/J, SWR/J, and the wild-derived PERA/EiJ. C58/J, NOD/LtJ, NZB/B1NJ, SJL/J, and PERA/EiJ demonstrated low sociability, measured by time spent in proximity to an unfamiliar conspecific, with 30-60% of mice from these strains showing social avoidance. In the Morris water maze, NZB/B1NJ had a persistent bias for the quadrant where the hidden platform was located during acquisition, even after 9 days of reversal training. A particularly interesting profile was found for C58/J, which had low social preference, poor performance in the T-maze, and overt motoric stereotypy. Overall, this set of tasks and observational methods provides a strategy for evaluating novel mouse models in behavioral domains relevant to the autism phenotype.     

A comparison of vestibular and auditory phenotypes in inbred mouse strains

The purposes of this research were to quantify gravity receptor function in inbred mouse strains and compare vestibular and auditory function for strain- and age-matched animals. Vestibular evoked potentials (VsEPs) were collected for 19 inbred strains at ages from 35 to 389 days old. On average, C57BL/6J (35 to 190 days), BALB/cByJ, C3H/HeSnJ, CBA/J, and young LP/J mice had VsEP thresholds comparable to normal. Elevated VsEP thresholds were found for elderly C57BL/6J, NOD.NONH2(kb), BUB/BnJ, A/J, DBA/2J, NOD/LtJ, A/WySnJ, MRL/MpJ, A/HeJ, CAST/Ei, SJL/J, elderly LP/J, and CE/J. These results suggest that otolithic function varies among inbred strains and several strains displayed gravity receptor deficits by 90 days old. Auditory brainstem response (ABR) thresholds were compared to VsEP thresholds for 14 age-matched strains. C57BL/6J mice (up to 190 days) showed normal VsEPs with normal to mildly elevated ABR thresholds. Four strains (BUB/BnJ, NOD/LtJ, A/J, elderly LP/J) had significant hearing loss and elevated VsEP thresholds. Four strains (DBA/2J, A/WySnJ, NOD.NONH2(kb), A/HeJ) had elevated VsEP thresholds (including absent VsEPs) with mild to moderate elevations in ABR thresholds. Three strains (MRL/MpJ, Ce/J, SJL/J) had significant vestibular loss with no concomitant hearing loss. These results suggest that functional change in one sensory system does not obligate change in the other. We hypothesize that genes responsible for early onset hearing loss may affect otolithic function, yet the time course of functional change may vary. In addition, some genetic mutations may produce primarily gravity receptor deficits. Potential genes responsible for selective gravity receptor impairment demonstrated herein remain to be identified.     

Behavioural responses to novelty in two inbred mouse strains after intrahippocampal naloxone and morphine

Male C57BL/6 and DBA/2 mice were injected intrahippocampally with either naloxone (0.5 μg) or morphine (1.0 μg), or saline vehicle alone and, after 15 min, some 12 behavioural components carried out in a novel environment were recorded for 20 min. Naloxone reduced exploratory rearing responses, wall-leaning and object-sniffing in strain C57BL/6 and augmented these behaviours in strain DBA/2, while morphine depressed the scores in both. In conjunction with previously obtained evidence that the mouse hippocampus contains a genotype-dependent cholinergic mechanism which regulates responses to novelty, these findings support the hypothesis that hippocampal opioid peptides modulate the cholinergic control of exploration in mice, possibly indirectly through GABAergic pathways. In contrast, locomotor activity, defaecation and tail elevation remained practically unaffected by the two drugs, and grooming showed another kind of genotype-treatment interaction, that is to say, after morphine.     

Genetic control of retinal projections in inbred strains of albino mice

Mutations in the tyrosinase gene are often associated with a misrouting of retinal ganglion cell axons at the optic chiasm. In albinos, tyrosinase activity is lost and some ganglion cell axons that would normally project into the ipsilateral optic tract instead cross midline and project into the contralateral tract. The developmental mechanisms that cause this modification in neuronal connectivity are unknown. In this study, we screened six diverse strains of albino mice (strains 129, A, AKR, BALB/c, C57BL/6-c/c, and CD-1) to discover genetically determined variations and possible gene loci that might affect the severity of the albino decussation abnormality. Ganglion cells were retrogradely labeled with horseradish peroxidase, and the ipsilaterally and contralaterally projecting cells were counted. The average number of ipsilaterally projecting ganglion cells in the six albino strains varies from 1,000 to 1,300. Despite this variation, 1.8–1.9% of the total population projects ipsilaterally in each strain. In comparison, 2.8% project ipsilaterally in the pigmented strain, C57BL/6-+/+. However, the percentage of displaced, ipsilaterally projecting cells varies substantially among albino strains-from a low of 4% in strain CD-1 to a high of nearly 10% in C57BL/6-c/c. We conclude that even with large differences in genetic background and in absolute numbers of ganglion cells, there is no appreciable variation in the magnitude of decussation error among albino mice. The consistent effect of null alleles at tyrosinase suggests a comparably tight linkage between the biochemical activity of this enzyme and the mechanisms that control decussation phenotype. © 1995 Wiley-Liss, Inc.     

Kainate and AMPA receptor binding in seizure-prone and seizure-resistant inbred mouse strains

Glutamate and its receptors represent the major excitatory neurotransmission system in the mammalian brain and are considered important in the pathogenesis of many neurological diseases. The present study describes saturation binding experiments performed to measure the affinity (K_d) and density (B_max) of kainate and AMPA receptors in striatum, cortex and hippocampus from mature DBA/2J (DBA) and C57BL/6J (C57) mice. Previous studies have documented that these two strains differ significantly in seizure susceptibility, with DBA mice exhibiting greater sensitivity in various convulsant tests compared to C57 mice. Non-linear regression analysis of binding data together with Student's t-test and ANOVA revealed significantly higher densities of kainate receptors in striatum and of AMPA receptors in cortex of DBA mice. C57 mice exhibited higher striatal [³H]AMPA binding. There were no significant differences between the mouse strains in binding sites prepared from hippocampus and no differences in affinity for either receptor in any brain region studied. The results support a role for kainate and AMPA receptors in seizure sensitivity, possibly by influencing glutamate transmission in specific pathways. It is unlikely, however, that these receptors account for the generation of seizures alone but rather cooperate with other glutamatergic and non-glutamatergic neurotransmitter systems.     

Hippocampal mossy fiber distributions and intermale aggression in seven inbred mouse strains

The capacity to initiate attack behavior against a passive standard opponent was measured in 140 male mice belonging to seven different inbred mouse strains. Large strain differences were found, which strongly correlated with the size of the hippocampal intra- and infrapyramidal mossy fibers terminal fields. These results, combined with those obtained from earlier experiments, point to a possible modulating role of the hippocampus in the regulation of attack behavior in male mice.     

Hippocampal mossy fiber distribution and long-term potentiation in two inbred mouse strains

We studied long-term potentiation in the inbred mouse strains DBA/2 and C3H/He known to be different in both hippocampal mossy fiber distribution and several aspects of learning. Tetanic stimulation of mossy fibers resulted in a significantly stronger increase of the population spike amplitude in the CA3 pyramidal cell layer of C3H mice. This result suggests that the extent of the CA3 hippocampal mossy fiber projection correlates with synaptic efficacy in mice.     

Dopamine synthesis in inbred mouse strains which differ in numbers of dopamine neurons

BALB/cJ and CBA/J mice have been shown to have different numbers of dopamine (DA) neurons in the central nervous system, with BALB/cJ mice having 20–50% more DA neurons in each dopaminergic cell group which is reflected in a difference in tyrosine hydroxylase activity in these cell groups. The present study compared the levels of DA and the rate of DA synthesis between these two inbred mouse strains. Three measures were used to reflect the rate of DA synthesis: the levels of DA metabolites (DOPAC and HVA) in the striatum, the rate of disappearance of DA following inhibition of tyrosine hydroxylase withα-methyl-P-tyrosine, and the rate of accumulation of DOPA following inhibition of aromatic amino acid decar☐ylase with NSD-1015. Striatal DA levels were slightly higher in CBA/J mice than BALB/cJ mice. The rate of DA synthesis in the striatum, as estimated from the accumulation of DOPA following NSD-1015 injection or from the decline of DA levels followingα-methyl-p-tyrosineinjection, was from 30–50% greater in the BALB/cJ mice compared to the CBA/J mice. In striatum, DOPAC levels were higher, HVA levels lower, and DOPAC plus HVA levels equal in CBA/J mice compared to BALB/cJ mice. The results show that BALB/cJ mice, with more DA neurons than CBA mice, also synthesize more DA. In addition, the data suggest that DA levels do not necessarily reflect numbers of DA neurons, and that catecholamine metabolite levels are not a good measure for comparing catecholamine synthesis between inbred animal strains.     

Influence of estrus cycle and ageing on activity patterns in two inbred mouse strains

Despite the widespread use of inbred mice in research, little is known about aging of the circadian system in female mice, although interactions between female gonadal hormones and circadian rhythms have been established. We investigated the influence of the estrus cycle on circadian aspects of running-wheel activity and changes in the course of aging in female C57BL/6 and C3H/He mice recorded continuously between the ages of 3 and 19 months. In the young, cycling mice the second part of the proestrus night was often, but not consistently, characterized by increased motor activity compared to the remaining estrus cycle nights. After estrus cycling had ceased in the course of ageing, the estrus-dependent day-to-day variability in activity was reduced. The amplitude of the daily rest-activity rhythm decreased progressively after the age of 8 months in C3H/He and 10 months in C57BL/6 mice. The capacity for resynchronisation of activity onset to the LD-cycle was compared in young and old mice after an 8-h phase advance of the LD-cycle. Resynchronisation was significantly slower in old C3H/He mice and unaffected by age in C57BL/6 mice. The circadian period in constant darkness did not change with age in either strain. However, the period was shorter in 17-month old C57BL/6 mice compared to an additional group, which was recorded at the same age, after at least 1-month adaptation to the recording conditions. The results show that the reproductive state as well as ageing influence motor activity patterns of female mice in a strain- and cohort-dependent manner.