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Cerebral Cortex (New York, N.Y. : 1991) May 2024Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother"... (Review)
Review
Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder.
Topics: Humans; Cerebellum; Autism Spectrum Disorder; Animals; Autistic Disorder; Purkinje Cells
PubMed: 38696597
DOI: 10.1093/cercor/bhae050 -
Journal of Integrative Neuroscience Aug 2023The cerebellum is an area of the brain that is prone to damage in individuals with Alzheimer's disease (AD). As a non-pharmacological intervention for AD, exercise...
BACKGROUND
The cerebellum is an area of the brain that is prone to damage in individuals with Alzheimer's disease (AD). As a non-pharmacological intervention for AD, exercise training has shown an ameliorating effect on AD pathology; however, the target regions have mostly been the cerebral cortex and hippocampus. The main aim of this study was to explore the influence of 12 weeks of treadmill running on the accumulation of AD-related proteins, dysfunction of mitochondria, and subsequent neuronal cell death in the cerebellum of triple transgenic (3xTg-AD) mice.
METHODS
Four-month-old 3xTg-AD mice were allocated into two groups: an AD control group (AD, n = 10) and an AD exercise group (AD-Exe, n = 10). The AD-Exe mice underwent training on a motorized animal treadmill 5 days a week for 12 weeks. After sacrifice, the cerebellum was collected and biochemically analyzed.
RESULTS
The AD-Exe mice expressed reduced levels of extracellular β-amyloid plaques and phosphorylated tau (p-tau), and showed improved Purkinje cell survival and mitochondrial function compared with AD mice.
CONCLUSIONS
These findings suggest that engaging in exercise training can offer protection against the progression of AD in the cerebellum by enhancing mitochondrial function and promoting cell survival.
Topics: Humans; Animals; Mice; Infant; Alzheimer Disease; Cell Survival; Cerebellum; Animals, Genetically Modified; Mitochondria
PubMed: 37735133
DOI: 10.31083/j.jin2205117 -
Genes To Cells : Devoted To Molecular &... Oct 2023The evolutionally conserved Cdc7 kinase plays crucial roles in initiation of DNA replication as well as in other chromosomal events. To examine the roles of Cdc7 in...
The evolutionally conserved Cdc7 kinase plays crucial roles in initiation of DNA replication as well as in other chromosomal events. To examine the roles of Cdc7 in brain development, we have generated mice carrying Cdc7 knockout in neural stem cells by using Nestin-Cre. The Cdc7 Nestin mice were born, but exhibited severe growth retardation and impaired postnatal brain development. These mice exhibited motor dysfunction within 9 days after birth and did not survive for more than 19 days. The cerebral cortical layer formation was impaired, although the cortical cell numbers were not altered in the mutant. In the cerebellum undergoing hypoplasia, granule cells (CGC) decreased in number in Cdc7 Nestin mice compared to the control at E15-18, suggesting that Cdc7 is required for DNA replication and cell proliferation of CGC at mid embryonic stage (before embryonic day 15). On the other hand, the Purkinje cell numbers were not altered but its layer formation was impaired in the mutant. These results indicate differential roles of Cdc7 in DNA replication/cell proliferation in brain. Furthermore, the defects of layer formation suggest a possibility that Cdc7 may play an additional role in cell migration during neural development.
Topics: Animals; Mice; Cell Cycle Proteins; Cerebellum; DNA Replication; Nestin; Protein Serine-Threonine Kinases
PubMed: 37584256
DOI: 10.1111/gtc.13059 -
JACC. Clinical Electrophysiology Dec 2023
Topics: Humans; Channelopathies; Electrophysiologic Techniques, Cardiac; Arrhythmias, Cardiac; Cardiac Electrophysiology
PubMed: 38151300
DOI: 10.1016/j.jacep.2023.11.003 -
Cerebellum (London, England) Feb 2024Elucidation of the mechanisms involved in neurodegenerative diseases of the cerebellum has been hampered by the lack of robust single cell models to study Purkinje...
Elucidation of the mechanisms involved in neurodegenerative diseases of the cerebellum has been hampered by the lack of robust single cell models to study Purkinje neurons and replicate at the same time in vivo features. Cerebellar Purkinje neurons are difficult to grow in dispersed cell culture, and only limited work has been done using rat cells. We developed a refined protocol for growing rat Purkinje neurons from embryonic and postnatal tissue ex vivo that results in well-developed, mature, functional, and synaptically active neurons. The rat Purkinje neurons generated are responsive to paracrine factors and genetic manipulation, allowing great experimental flexibility at the single-cell level. This ex vivo model can be used to investigate disease mechanisms that disturb Purkinje neuron morphology, function, and communication in high- and low-throughput screening formats.
Topics: Rats; Animals; Purkinje Cells; Cerebellum; Neurons; Cell Culture Techniques
PubMed: 36626013
DOI: 10.1007/s12311-022-01510-4 -
Scientific Reports Jul 2023Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in...
Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.
Topics: Female; Male; Animals; Mice; Autistic Disorder; Autism Spectrum Disorder; Valproic Acid; Diet; Fatty Acids, Unsaturated; Fatty Acids, Omega-3; Dietary Supplements
PubMed: 37433863
DOI: 10.1038/s41598-023-38423-z -
BioRxiv : the Preprint Server For... Feb 2024Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje...
Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic duplication with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties, and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional knockout (KO and cKO, respectively) mouse lines. KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in cKO animals. By Golgi staining, KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a significant increase in Bergmann glia volume in the molecular layer of KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
PubMed: 38405978
DOI: 10.1101/2024.02.18.580354 -
Cerebellum (London, England) Aug 2023There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous...
There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous genetic mutations in rats and mice, engineered genetic alleles in mice, shRNA knockdown in mice, and conditional genetic silencing of fast neurotransmission in mice have all uncovered a common set of behavioral and electrophysiological defects that point to cerebellar cortical and cerebellar nuclei dysfunction as a source of dystonic phenotypes. Here, we revisit the Ptf1a;Vglut2 mutant mouse to define fundamental phenotypes and measures that are valuable for testing the cellular, circuit, and behavioral mechanisms that drive dystonia. In this model, excitatory neurotransmission from climbing fibers is genetically eliminated and, as a consequence, Purkinje cell and cerebellar nuclei firing are altered in vivo, with a prominent and lasting irregular burst pattern of spike activity in cerebellar nuclei neurons. The resulting impact on behavior is that the mice have developmental abnormalities, including twisting of the limbs and torso. These behaviors continue into adulthood along with a tremor, which can be measured with a tremor monitor or EMG. Importantly, expression of dystonic behavior is reduced upon cerebellar-targeted deep brain stimulation. The presence of specific combinations of disease-like features and therapeutic responses could reveal the causative mechanisms of different types of dystonia and related conditions. Ultimately, an emerging theme places cerebellar dysfunction at the center of a broader dystonia brain network.
Topics: Mice; Rats; Animals; Dystonia; Tremor; Cerebellum; Purkinje Cells; Dystonic Disorders; Cerebellar Diseases
PubMed: 35821365
DOI: 10.1007/s12311-022-01441-0 -
BioRxiv : the Preprint Server For... Nov 2023Cerebellar damage early in life often causes long-lasting motor, social, and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum...
Cerebellar damage early in life often causes long-lasting motor, social, and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviors. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviors. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is the direct postsynaptic target of the cerebellum, sending cerebellar outputs to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The hemizygous deletion of the tuberous sclerosis complex-1 ( ) gene in the Purkinje cell-known to cause Purkinje cell hypoactivity and autistic behaviors-did not alter cerebellothalamic synapses or intrinsic membrane properties of thalamic neurons. However, the ablation of Purkinje cells in the developing cerebellum strengthened the cerebellothalamic synapses and enhanced thalamic suprathreshold activities. These results suggest that the cerebellothalamic circuit is resistant to moderate perturbation in the developing cerebellum, such as the reduced firing rate of Purkinje cells, and that autistic behaviors are not necessarily linked to thalamic abnormality. Still, Purkinje cell loss alters the thalamic circuit, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum.
PubMed: 37961231
DOI: 10.1101/2023.11.01.564864 -
Scientific Reports Nov 2023Adenosine kinase (ADK), the major adenosine-metabolizing enzyme, plays a key role in brain development and disease. In humans, mutations in the Adk gene have been linked...
Adenosine kinase (ADK), the major adenosine-metabolizing enzyme, plays a key role in brain development and disease. In humans, mutations in the Adk gene have been linked to developmental delay, stunted growth, and intellectual disability. To better understand the role of ADK in brain development, it is important to dissect the specific roles of the two isoforms of the enzyme expressed in the cytoplasm (ADK-S) and cell nucleus (ADK-L). We, therefore, studied brain development in Adk-tg transgenic mice, which only express ADK-S in the absence of ADK-L throughout development. In the mutant animals, we found a reduction in the overall brain, body size, and weight during fetal and postnatal development. As a major developmental abnormality, we found a profound change in the foliation pattern of the cerebellum. Strikingly, our results indicated aberrant Purkinje cells arborization at P9 and accelerated cell death at P6 and P9. We found defects in cerebellar cell proliferation and migration using a bromodeoxyuridine (BrdU)-based cell proliferation assay at postnatal day 7. Our data demonstrate that dysregulation of ADK expression during brain development profoundly affects brain growth and differentiation.
Topics: Mice; Animals; Humans; Adenosine Kinase; Brain; Mice, Transgenic; Cerebellum; Protein Isoforms
PubMed: 37963945
DOI: 10.1038/s41598-023-47098-5