Ablation of Lhx15 Gene Expression in Cerebellar Purkinje Cells Delay Peripheral Nervous System Regeneration
DescriptionAxons (make up the nerves) of the peripheral nervous system are capable of regrowth, albeit at aslow rate (1-2mm/day) and generally incomplete. Peripheral nerve injury (PNI) could result in amultitude of changes in patients including sensory and motor dysfunction, pain and associatedemotional disorders, which greatly affect a patient’s quality of life. This is particular evident forchanges in cortical neurocircuitry (cortical synaptic plasticity) in patients examined by brainimaging, however, how cortical synaptic plasticity contributes to functional recovery after injuryremains largely unknown.Cerebellum is the fine movement coordination center which contains over 50% of total numberof neurons in the brain. Purkinje cells (PCs) are one of the major neurons in the cerebellum andthe sole output neuron for fine-tuning motor activity. Recent studies showed that both LIM-homeodomaintranscription factors Lhx1 and Lhx5 are required for the development anddifferentiation of PCs since Lhx1/5 double knockout (DKO) mice are embryonic lethal.A conditional Lhx1/5 DKO mouse ablating Lhx1/5 expression specifically in mature PCs wasgenerated without showing any loss of PCs. Mild thinner dendrite of PCs, abnormal formation ofdendritic spines, and downregulating of several synaptic genes were observed in theseconditional DKO mutants. We therefore hypothesize that Lhx1/5 cerebellar expression is crucialfor synaptic plasticity and motor functional recovery. To test this hypothesis, we performed PNIon conditional DKO mice and assessed functional recovery with an exhaustive list of behaviourtests for 2 months and the motor functional recovery was reduced significantly in DKO mutants.In consistence with our behaviour studies, muscle strength of conditional DKO mutants wassignificantly lower as measured by electromyography (EMG). Our preliminary data clearlydemonstrated the link between cerebellar Lhx1/5 expression and functional recovery. In currentproposal, we will extend these findings to synaptic plasticity studies by using animal models ofPNIs to examine temporal dynamic of synapse formation in target muscle and cerebellum. Ourongoing studies showed that the electroencephalography (EEG) signal of deep cerebellar nuclei(DCN) is reduced in uninjured DKO mutant but further electrophysiological studies includingmulti-electrode arrays and single cell recordings will be performed to better understand neuronalplasticity after injury. The gene expression profile studies will identify key genes that alter thecortical plasticity and regenerative capacity of injured neurons. Knowledge obtained fromcurrent project will provide insight into the development of neuroprosthetics andneurorehabilitation strategies for treating traumatic PNIs or other brain injuries.
|Effective start/end date||1/01/16 → 27/12/19|
- Peripheral nervous system,Dorsal root ganglion,Intrinsic growth capacity,Neuroregeneration,