Biology subjects

Pasterkamp, J.

Publications and source records attributed to Pasterkamp, J..

3 recordsLinked to original sources

bioRxiv2025

Motor Cortex Modulates Ipsilateral Limb Movement Through a Direct Cortico-Cerebellar Circuit

Motor cortex is traditionally associated with control of contralateral limb movements via corticospinal and cortico-ponto-cerebellar pathways. However, the contribution of ipsilateral motor cortical outputs on motor control remains unclear. Here, we identify and characterize a distinct population of cortico-cerebellar (C-C) neurons in the motor cortex that form monosynaptic projections to the ipsilateral cerebellar nuclei. The C-C neurons receive preferential local motor cortical inputs and exhibit projection patterns distinct from cortico-pontine projecting neurons. Using in vivo imaging and optogenetic perturbations, we show that these neurons are active during locomotion and transitions of volitional movements. Disruption of the C-C projection severely affects the locomotion and balancing. Interestingly, the C-C pathway is selectively involved in the initiation and coordination of ipsilateral forelimb movements, without affecting contralateral movement kinematics. These findings shed light on a non-canonical cortico-cerebellar pathway that supports ipsilateral motor control, complementing the traditional control mechanisms of the cerebral cortex over the contralateral motor domains.

neuroscience↗

bioRxiv2023

Semaphorin 6A in Retinal Ganglion Cells Regulates Functional Specialization of the Inner Retina

To form functional circuits, neurons must settle in their appropriate cellular locations and then project and elaborate neurites to contact their target synaptic neuropils. Laminar organization within the vertebrate retinal inner plexiform layer (IPL) facilitates pre- and postsynaptic neurite targeting, yet, the precise mechanisms underlying establishment of functional IPL subdomains are not well understood. Here we explore mechanisms defining the compartmentalization of OFF and ON neurites generally, and OFF and ON direction-selective neurites specifically, within the developing IPL. We show that semaphorin 6A (Sema6A), a repulsive axon guidance cue, is required for delineation of OFF versus ON circuits within the IPL: in the Sema6a null IPL, the boundary between OFF and ON domains is blurred. Furthermore, Sema6A expressed by retinal ganglion cells (RGCs) directs laminar segregation of OFF and ON starburst amacrine cell (SAC) dendritic scaffolds, which themselves serve as a substrate upon which other retinal neurites elaborate. These results demonstrate for the first time that RGCs, the first neuron-type born within the retina, play an active role in functional specialization of the IPL. Retinal ganglion cell-dependent regulation of OFF and ON starburst amacrine cell dendritic scaffold segregation prevents blurring of OFF versus ON functional domains in the murine inner plexiform layer.

neuroscience↗

bioRxiv2019

Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-function C9ORF72 ALS/FTD disease processes in vivo

The most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) in C9ORF72 that contributes to neurodegeneration by both loss-of-function (decreased C9ORF72 protein levels) and gain-of-function (e.g. dipeptide repeat protein production) mechanisms. Although therapeutics targeting the gain-of-function mechanisms are in clinical development, it is unclear if these will be efficacious given the contribution of C9ORF72 loss-of-function processes to neurodegeneration. Moreover, there is a lack of therapeutic strategies for C9ORF72 ALS/FTD with demonstrated efficacy in vivo. Here, we show that small molecule inhibition of PIKFYVE kinase rescues both loss- and gain-of-function C9ORF72 disease mechanisms in vivo. We find that the reduction of C9ORF72 in mouse motor neurons leads to a decrease in early endosomes. In contrast, treatment with the PIKFYVE inhibitor apilimod increases the number of endosomes and lysosomes. We show that reduced C9ORF72 levels increases glutamate receptor levels in hippocampal neurons in mice, and that apilimod treatment rescues this excitotoxicity-related phenotype in vivo. Finally, we show that apilimod also alleviates the gain-of-function pathology induced by the C9ORF72 HRE by decreasing levels of dipeptide repeat proteins derived from both sense and antisense C9ORF72 transcripts in hippocampal neurons in vivo. Our data demonstrate the neuroprotective effect of PIKFYVE kinase inhibition in both gain- and loss-of-function murine models of C9ORF72 ALS/FTD.

neuroscience↗