Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations

Nguon, K.; Ladd, Byron; Baxter, Mark G.; Sajdel-Sulkowska, Elizabeth M.

doi:10.1016/s0079-6123(04)48027-3

Cited by 44 publications

(36 citation statements)

References 71 publications

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“…Instead, P-Rex may be able respond to sexually dimorphic inputs. The mechanisms governing sex differences in cerebellar development leading to dimorphic motor behavior are unknown (36). In general, sex differences arise from the complex combined effects of gonadal hormone signaling, sex-chromosomespecific gene expression, sexually dimorphic autosomal gene expression, and imprinting (37).…”

Section: Discussionmentioning

confidence: 99%

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Donald

Humby²,

Fyfe³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /PRex2 ؊/؊ mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2 ؊/؊ pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice. P-Rex2 ؊/؊ mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.G protein-coupled receptor ͉ guanine-nucleotide exchange factor ͉ phosphoinositide-3-kinase ͉ small GTPase Rac ͉ ataxia T he small GTPase Rac (isoforms 1, 2, and 3) controls the structure of the actomyosin cytoskeleton, gene expression, and reactive oxygen species (ROS) formation (1). In the nervous system, Rac is essential for all stages of neuronal development (neurite, axon, and dendrite formation, axon pathfinding, dendrite branching and dendritic spine formation, and survival), as shown by manipulations of Rac activity in the nervous system of animals, neuronal cell lines, and primary cultures (2).Deletion of the ubiquitous Rac1 from the mouse, whether total or specifically in the brain, is embryonic lethal (3, 4), but transgenic overexpression of constitutively active Rac1 in the Purkinje neurons of the cerebellum results in severe ataxia, with animals unable to walk in a straight line and poor performance on the rotarod (5). Similarly, deletion of nervous system-specific Rac3 results in an increased ability for learning and coordination of skilled movements (6), deletion of the Rac-GAP ␣-Chimerin induces a hopping gait due to misguidance of corticospinal tract axons (7), and deletion of the brain-specific form of the Rac-effector Wave, which links Rac to the actin cytoskeleton, causes defects in motor coordination, learning, and memory (8).Like all small GTPases, Rac is activated by guanine-nucleotide exchange factors (GEFs) (9). Several Rac-GEFs are known to control neuronal development: Tiam1/Stef regulates neurite and axon outgrowth and dendritic spine formation (2, 10); Vav2 and Vav3 control axon outgrowth from retina to thalamus (11); Trio governs neurite outgrowth, axon extension, and pathfinding (2); Kalirin regulates neurite and axon outgrowth and dendritic spine formation (2); Dock180 controls neurite ou...

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Section: Discussionmentioning

confidence: 99%

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Donald

Humby²,

Fyfe³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In hamsters, glial fibrillary acidic protein (GFAP) staining is more intense in males, whereas vimentin staining in the Bergman glia is more intense in females both during development and in adulthood (11). Rats show a similar difference in glial staining (12). Although this suggests the possibility of differences in the regulation of glial development between the sexes, the functional significance is not clear.…”

Section: The Cerebellum: a Sexually Dimorphic Area?mentioning

confidence: 99%

“…Energy use differences may also exist in animal models; male rats have higher creatinine kinase activity than females, but females display a greater variety of creatinine kinase isoenzymes (15). Behaviorally, inbred mouse strain females show greater improvement in active rotation scores than males after three days (16), but this was not replicated in healthy rats (12). Human females need approximately 50 ms longer to make unexpected 90 degree turns while walking at all ages (17).…”

Section: The Cerebellum: a Sexually Dimorphic Area?mentioning

confidence: 99%

Steroids, sex and the cerebellar cortex: implications for human disease

Dean

McCarthy

2008

Cerebellum

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Neurosteroids play an important role in the development of the cerebellum. In particular, estradiol and progesterone appear capable of inducing increases in dendritic spine density during development, and there is evidence that both are synthesized de novo in the cerebellum during critical developmental periods. In normal neonates and adults, there are few differences in the cerebellum between the sexes and most studies indicate that hormone and receptor levels also do not differ significantly during development. However, the sexes do differ significantly in risk of neuropsychological diseases associated with cerebellar pathology, and in animal models there are noticeable sex differences in the response to insult and genetic mutation. In both humans and animals, males tend to fare worse. Boys are more at risk for autism and Attention Deficit Hyperactivity Disorder than girls, and schizophrenia manifests at an earlier age in men. In rats males fare worse than females after perinatal exposure to polychlorinated biphenyls, and male mice heterozygous for the staggerer and reeler mutation show a more severe phenotype. Although very recent evidence suggests that differences in neurosteroid levels between the sexes in diseased animals may play a role in generating different disease phenotypes, the reason this hormonal difference occurs in diseased but not normal animals is currently unknown.

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“…According to Dean and McCarthy (10), the sex-dependent differences are not related to the basal amounts of neurosteroids or receptors but to the differential regulation of their levels following environmental insults. Moreover, perinatal exposure to chemical toxins affects neurodevelopment, motor coordination, and behavior differently in males and females, in line with sex-dependent changes in cerebellar protein expression (32). Such dimorphic variations could account for the sex-dependent prevalence of some neuropsychological disorders, like depression or schizophrenia, in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups

Chehadeh

Dreumont

Willekens

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups. Am J Physiol Endocrinol Metab 307: E1009 -E1019, 2014. First published October 7, 2014; doi:10.1152/ajpendo.00364.2014.-Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ER␣, ER␤, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex-dependent manner. early methyl donor deficiency; neurosteroids; cerebellum development; cyclic AMP signaling cascade DEFICIENCY OF METHYL DONORS (folate and vitamin B12) involved in the one-carbon metabolism and the consecutive accumulation of the neurotoxic amino acid homocysteine (HCY) have been associated with various neurological diseases (33). A loss of cerebellar granule cells along with HCY accumulation was reported in a transgenic model of mice deficient in methylenetetrahydrofolate reductase, a key enzyme of the one-carbon metabolism. This observation is of particular interest since the accumulation of HCY in the brain appeared to be heterogeneous, with the cerebellum displaying a higher amount than other cerebral regions (6).In a validated animal model based on rats born to dams fed a diet deficient in methyl donors during the gestational and lactating periods (2-5), the 21-day-old progeny showed a marked accumulation of HCY, along with increased apoptosis in selective brain structures, notably the cerebellum (5). At the time of weaning, animals exhibited cognitive and motor defects, and it has been reported that methyl donor privation during early life is associated with alteration of synaptic plasticity and impaired neurogenesis (9), pro...

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Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations

Cited by 44 publications

References 71 publications

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Steroids, sex and the cerebellar cortex: implications for human disease

Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups

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