Nogo-A neutralization in the central nervous system with a blood-brain barrier-penetrating antibody.

The poor penetration of monoclonal antibodies (mAb) across the blood-brain barrier (BBB) impedes the development of regenerative therapies for neurological diseases. For example, Nogo-A is a myelin-associated protein highly expressed in the central nervous system (CNS) whose inhibitory effects on neuronal plasticity can be neutralized with direct administration of 11C7 mAb in CNS tissues/fluids, but not with peripheral administrations such as intravenous injections. Therefore, in the present study, we engineered a CNS-penetrating antibody against Nogo-A by combining 11C7 mAb and the single-chain variable fragment (scFv) of 8D3, a rat antibody binding transferrin receptor 1 (TfR) and mediating BBB transcytosis (11C7-scFv8D3).

Subthalamic lesion or levodopa treatment rescues giant GABAergic currents of PINK1-deficient striatum.

Cellular electrophysiological signatures of Parkinson's disease described in the pharmacological 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease include spontaneous repetitive giant GABAergic currents in a subpopulation of striatal medium spiny neurons (MSNs), and spontaneous rhythmic bursts of spikes generated by subthalamic nucleus (STN) neurons. We investigated whether similar signatures are present in Pink1(-/-) mice, a genetic rodent model of the PARK6 variant of Parkinson's disease. Although 9- to 24-month-old Pink1(-/-) mice show reduced striatal dopamine content and release, and impaired spontaneous locomotion, the relevance of this model to Parkinson's disease has been questioned because mesencephalic dopaminergic neurons do not degenerate during the mouse lifespan.

Midbrain dopaminergic neurons generate calcium and sodium currents and release dopamine in the striatum of pups.

Midbrain dopaminergic neurons (mDA neurons) are essential for the control of diverse motor and cognitive behaviors. However, our understanding of the activity of immature mDA neurons is rudimentary. Rodent mDA neurons migrate and differentiate early in embryonic life and dopaminergic axons enter the striatum and contact striatal neurons a few days before birth, but when these are functional is not known.