Abstract
Eph receptor tyrosine kinases are involved in many cellular processes. In the developing brain, they act as migratory and cell adhesive cues while in the adult brain they regulate dendritic spine plasticity. Here we show a new role for Eph receptor signalling in the cerebellar cortex. Cerebellar Purkinje cells are innervated by two different excitatory inputs. The climbing fibres contact the proximal dendritic domain of Purkinje cells, where synapse and spine density is low; the parallel fibres contact the distal dendritic domain, where synapse and spine density is high. Interestingly, Purkinje cells have the intrinsic ability to generate a high number of spines over their entire dendritic arborisations, which can be innervated by the parallel fibres. However, the climbing fibre input continuously exerts an activity-dependent repression on parallel fibre synapses, thus confining them to the distal Purkinje cell dendritic domain. Such repression persists after Eph receptor activation, but is overridden by Eph receptor inhibition with EphA4/Fc in neonatal cultured cerebellar slices as well as mature acute cerebellar slices, following in vivo infusion of the EphA4/Fc inhibitor and in EphB receptor-deficient mice. When electrical activity is blocked in vivo by tetrodotoxin leading to a high spine density in Purkinje cell proximal dendrites, stimulation of Eph receptor activation recapitulates the spine repressive effects of climbing fibres. These results suggest that Eph receptor signalling mediates the repression of spine proliferation induced by climbing fibre activity in Purkinje cell proximal dendrites. Such repression is necessary to maintain the correct architecture of the cerebellar cortex.
Highlights
Ephrin ligands and their receptors, the Eph receptor (Eph) tyrosine kinases, are cell surface molecules that mediate communication between cells
Activation of class A and B Eph receptors in neonatal cerebellar slice cultures does not affect dendritic spine density in Purkinje cells In a first group of experiments, we altered Eph/ephrin signalling during development in organotypic slices from the P10 cerebellum of L7-EGFP mice, which express enhanced green fluorescent protein (EGFP) in Purkinje cells
At P10–P11 Purkinje cell dendrites have already developed a proximal compartment with very low spine density and a distal compartment that is densely covered by spines that are contacted by parallel fibres [19]
Summary
Ephrin ligands and their receptors, the Eph receptor (Eph) tyrosine kinases, are cell surface molecules that mediate communication between cells. Ephrins and Eph receptors are especially highly expressed in the embryonic nervous system, where their signalling is important for proper axonal pathfinding and to establish topographic projections [1,2,3]. They maintain a remarkable presence in the adult brain, especially in regions characterized by a high degree of structural plasticity in adulthood, such as the hippocampus, olfactory bulb and cerebellum [2,4,5,6]. Eph receptors can be found in presynaptic terminals [3,13] and their cell surface expression can be regulated by synaptic activity [14]
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