Social memory deficit caused by dysregulation of the cerebellar vermis

Chao, Owen Y.; Pathak, Salil Saurav; Zhang, Hao; Augustine, George J.; Christie, Jason M.; Kikuchi, Chikako; Taniguchi, Hiroki; Yang, Yi-Mei

doi:10.1038/s41467-023-41744-2

Cited by 13 publications

(3 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the role of the cerebellum in emotional processes has largely been understudied, but recent imaging research findings in humans show evidence of hyperactivity both in the cerebellum and amygdala in social anxiety disorder [52,53], higher cerebellar baseline activity in panic disorder [54] and increased cerebellar activity in post-traumatic stress disorder [55]. Recently, anatomical tracing of mouse brain revealed hierarchical projections from the cerebellum to the social brain network, including amygdalar connections [56].…”

Section: Discussionmentioning

confidence: 99%

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

Vacca,

Zarrouki,

Izabelle

et al. 2024

Cells

View full text Add to dashboard Cite

A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities in Duchenne muscular dystrophy (DMD). Recent advances in preclinical research have achieved some success in compensating both muscle and brain dysfunctions associated with DMD, notably using exon skipping strategies. However, this has not been studied for distal mutations in the DMD gene leading to Dp71 loss. In this study, we aimed to restore brain Dp71 expression in the Dp71-null transgenic mouse using an adeno-associated virus (AAV) administrated either by intracardiac injections at P4 (ICP4) or by bilateral intracerebroventricular (ICV) injections in adults. ICP4 delivery of the AAV9-Dp71 vector enabled the expression of 2 to 14% of brain Dp71, while ICV delivery enabled the overexpression of Dp71 in the hippocampus and cortex of adult mice, with anecdotal expression in the cerebellum. The restoration of Dp71 was mostly located in the glial endfeet that surround capillaries, and it was associated with partial localization of Dp71-associated proteins, α1-syntrophin and AQP4 water channels, suggesting proper restoration of a scaffold of proteins involved in blood–brain barrier function and water homeostasis. However, this did not result in significant improvements in behavioral disturbances displayed by Dp71-null mice. The potential and limitations of this AAV-mediated strategy are discussed. This proof-of-concept study identifies key molecular markers to estimate the efficiencies of Dp71 rescue strategies and opens new avenues for enhancing gene therapy targeting cognitive disorders associated with a subgroup of severely affected DMD patients.

show abstract

Section: Discussionmentioning

confidence: 99%

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

Vacca,

Zarrouki,

Izabelle

et al. 2024

Cells

View full text Add to dashboard Cite

show abstract

“…Although Purkinje cells spontaneously discharge action potentials, their firing rate is modulated by excitatory and inhibitory synaptic inputs. Inhibitory inputs are provided by interneurons in the cerebellar molecular layer (MLI), and chemogenetic excitation and inhibition of MLI both lead to impaired social behavior in mice (Badura et al ., 2018; Chao et al ., 2023). These results suggest that aberrant Purkinje cell activity is not a coincidence but a cause of social and cognitive impairments.…”

Section: Discussionmentioning

confidence: 99%

“…The link between the cerebellum and cognitive impairments in these disorders previously seemed perplexing because the cerebellum was traditionally considered a part of the motor system. However, recent studies show that the cerebellum is also involved in various non-motor functions, such as cognitive processing, social behavior, fear, and emotion, through its interaction with other brain regions (Koziol et al ., 2014; Palesi et al ., 2015; Badura et al ., 2018; Vaaga et al ., 2020; Fastenrath et al ., 2022; Chao et al ., 2023).…”

Section: Introductionmentioning

confidence: 99%

Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses

Nishiyama,

Zemelman

2023

Preprint

View full text Add to dashboard Cite

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 (Tsc1) 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.

show abstract

Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice

van der Heijden

2024

Cerebellum

View full text Add to dashboard Cite

Evidence from clinical and preclinical studies has shown that the cerebellum contributes to cognitive functions, including social behaviors. Now that the cerebellum’s role in a wider range of behaviors has been confirmed, the question arises whether the cerebellum contributes to social behaviors via the same mechanisms with which it modulates movements. This review seeks to answer whether the cerebellum guides motor and social behaviors through identical pathways. It focuses on studies in which cerebellar cells, synapses, or genes are manipulated in a cell-type specific manner followed by testing of the effects on social and motor behaviors. These studies show that both anatomically restricted and cerebellar cortex-wide manipulations can lead to social impairments without abnormal motor control, and vice versa. These studies suggest that the cerebellum employs different cellular, synaptic, and molecular pathways for social and motor behaviors. Future studies warrant a focus on the diverging mechanisms by which the cerebellum contributes to a wide range of neural functions.

show abstract

Social memory deficit caused by dysregulation of the cerebellar vermis

Cited by 13 publications

References 76 publications

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses

Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice

Contact Info

Product

Resources

About