Eph/ephrin Function Contributes to the Patterning of Spinocerebellar Mossy Fibers Into Parasagittal Zones

Lackey, Elizabeth P.; Sillitoe, Roy V.

doi:10.3389/fnsys.2020.00007

Cited by 10 publications

(9 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). Granule cell neurogenesis is promoted by the earlier-born Purkinje cells [38, 39], and with the exponential expansion of the granule cell population, the cerebellum ultimately increases approximately 5-fold in size. As a consequence of this, there is a remarkable increase in the complexity of its folding patterns (shown in Fig.…”

Section: Development Of the Cerebellar Circuitmentioning

confidence: 99%

Abnormal Cerebellar Development in Autism Spectrum Disorders

2021

Self Cite

View full text Add to dashboard Cite

Autism spectrum disorders (ASD) comprise a group of heterogeneous neurodevelopmental conditions characterized by impaired social interactions and repetitive behaviors with symptom onset in early infancy. The genetic risks for ASD have long been appreciated: concordance of ASD diagnosis may be as high as 90% for monozygotic twins and 30% for dizygotic twins, and hundreds of mutations in single genes have been associated with ASD. Nevertheless, only 5–30% of ASD cases can be explained by a known genetic cause, suggesting that genetics is not the only factor at play. More recently, several studies reported that up to 40% of infants with cerebellar hemorrhages and lesions are diagnosed with ASD. These hemorrhages are overrepresented in severely premature infants, who are born during a period of highly dynamic cerebellar development that encompasses an approximately 5-fold size expansion, an increase in structural complexity, and remarkable rearrangements of local neural circuits. The incidence of ASD-causing cerebellar hemorrhages during this window supports the hypothesis that abnormal cerebellar development may be a primary risk factor for ASD. However, the links between developmental deficits in the cerebellum and the neurological dysfunctions underlying ASD are not completely understood. Here, we discuss key processes in cerebellar development, what happens to the cerebellar circuit when development is interrupted, and how impaired cerebellar function leads to social and cognitive impairments. We explore a central question: Is cerebellar development important for the generation of the social and cognitive brain or is the cerebellum part of the social and cognitive brain itself?

show abstract

Section: Development Of the Cerebellar Circuitmentioning

confidence: 99%

Abnormal Cerebellar Development in Autism Spectrum Disorders

2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…During development, these projections directly target Purkinje cells ( Kalinovsky et al, 2011 ; Sillitoe, 2016 ), but with the integration of granule cells into the circuit, mossy fibers displace their synapses onto granule cells ( Arsénio Nunes et al, 1988 ; Pan et al, 2009 ). To test how this sequence of events was impacted by the lack of granule cells in En1 Cre/+ ;Atoh1 fl/- mice, we injected the anterograde tracer WGA-Alexa 555 into the lower thoracic-upper lumbar spinal cord of P12 mice ( Gebre et al, 2012 ; Lackey and Sillitoe, 2020 ). We observed WGA-Alexa 555 labeled fibers and terminals at P14 after two days of tracer transport.…”

Section: Resultsmentioning

confidence: 99%

“…Anterograde neuroanatomical tracing of mossy fibers to the cerebellum was performed as described previously ( Lackey and Sillitoe, 2020 ; Sillitoe, 2016 ). P12 pups were anesthetized with isoflurane on a surgery rig.…”

Section: Methodsmentioning

confidence: 99%

Maturation of Purkinje cell firing properties relies on neurogenesis of excitatory neurons

Heijden

Lackey

Perez

et al. 2021

eLife

View full text Add to dashboard Cite

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Excitatory granule cells, the most numerous neuron type in the brain, are especially vulnerable and likely instigate disease by impairing the function of their targets, the Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether excitatory neurons establish the firing properties of Purkinje cells during postnatal mouse development. We generated mutant mice that lack the majority of excitatory cerebellar neurons and tracked the structural and functional consequences on Purkinje cells. We reveal that Purkinje cells fail to acquire their typical morphology and connectivity, and that the concomitant transformation of Purkinje cell firing activity does not occur either. We also show that our mutant pups have impaired motor behaviors and vocal skills. These data argue that excitatory cerebellar neurons define the maturation time-window for postnatal Purkinje cell functions and refine cerebellar-dependent behaviors.

show abstract

“…Neuroanatomical anterograde tracing: Anterograde neuroanatomical tracing of mossy fibers to the cerebellum were performed as described previously (Lackey and Sillitoe, 2020;Sillitoe, 2016). P12 pups were anesthetized with isoflurane on a surgery rig.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, there was dense staining for Vglut2-positive inputs to cerebellar and displaced Purkinje cells (Figure 2C; climbing fibers/mossy fibers). To test if some inputs were from the spinal cord that sends an early major cerebellar projection, we injected the anterograde tracer WGA-Alexa 555 (Gebre et al, 2012;Lackey and Sillitoe, 2020) into the lower thoracic-upper lumbar spinal cord of P12 mice and observed WGA-Alexa 555 labeled fibers and terminals at P14 after two days of tracer transport. In control cerebella, mossy fibers project to the cerebellar cortex in a striped pattern that respects the topography of ZebrinII, a molecular marker of medial-lateral Purkinje cell patterns (Figure 2D, E and Supp.…”

Section: Purkinje Cells In En1mentioning

confidence: 99%

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

Heijden

Lackey

Işleyen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

37Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive 38 difficulty. Granule cells are especially vulnerable, and they likely instigate disease by impairing 39 the function of Purkinje cells. Here, we use regional genetic manipulations and in vivo 40 electrophysiology to test whether granule cells help establish the firing properties of Purkinje 41 cells during postnatal mouse development. We generated mice that lack granule cell 42 neurogenesis and tracked the structural and functional consequences on Purkinje cells in these 43 agranular pups. We reveal that Purkinje cells fail to acquire their typical connectivity and 44 morphology, and the formation of characteristic Purkinje cell firing patterns is delayed by one 45 week. We also show that the agranular pups have impaired motor behaviors and vocal skills. 46 These data argue that granule cell neurogenesis sets the maturation time window for Purkinje cell 47 51 Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders 52 including ataxia, dystonia, tremor, and autism. These conditions are highly prevalent in 53 premature infants and in newborns with cerebellar hemorrhage (Dijkshoorn et al., 2020; 54 Limperopoulos et al., 2007; Steggerda et al., 2009; Zayek et al., 2012), who ultimately attain a 55 smaller cerebellar size compared to children born full-term (Limperopoulos et al., 2005; Volpe, 56 2009). During the third trimester of human development, which corresponds to the first two 57 postnatal weeks in mice (Sathyanesan et al., 2019), the cerebellum increases five-fold in size due 58 to the rapid proliferation of granule cell precursors and the integration of granule cells into the 59 cerebellar circuit (Chang et al., 2000). Observations from clinical data indicate a strong 60 correlation between cerebellar size and cognitive disorders, suggesting that this period of 61 cerebellar expansion is a critical developmental time-window for establishing cerebellar 62 function. Pig and mouse studies confirm that preterm birth, postnatal hemorrhage and hypoxia all 63 result in lower granule cell numbers (Iskusnykh et al., 2018; Yoo et al., 2014) and abnormal 64 motor control (Sathyanesan et al., 2018; Yoo et al., 2014). Importantly, such peri-and postnatal 65 insults are accompanied by impairments in the intrinsic firing properties of Purkinje cells 66 (Sathyanesan et al., 2018). Purkinje cells are the sole output of the cerebellar cortex and integrate 67 input from up to two hundred fifty thousand excitatory granule cell synapses (Huang et al., 68 2014), though the predominant Purkinje cell action potential called the simple spike, is 69 intrinsically generated (Raman and Bean, 1999). In this context, it is intriguing that genetically 70 silencing granule cells caused modest alterations to the baseline firing properties of Purkinje 71 cells and impaired only the finer aspects of motor learning, but not gross motor control (Galliano 72 et al., 2013). The discordance between the p...

show abstract

Eph/ephrin Function Contributes to the Patterning of Spinocerebellar Mossy Fibers Into Parasagittal Zones

Cited by 10 publications

References 90 publications

Abnormal Cerebellar Development in Autism Spectrum Disorders

Abnormal Cerebellar Development in Autism Spectrum Disorders

Maturation of Purkinje cell firing properties relies on neurogenesis of excitatory neurons

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

Contact Info

Product

Resources

About