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Lurcher Mice Exhibit Potentiation of GABA_A-Receptor–Mediated Conductance in Cerebellar Nuclei Neurons in Close Temporal Relationship to Purkinje Cell Death

Department of Cognitive Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany

Submitted 21 February 2003; accepted in final form 2 October 2003

In heterozygous Lurcher mice (Lc/+), the Purkinje cells (PCs) degenerate almost totally during postnatal development. On the other hand, their projection target, the deep cerebellar nuclei (DCN), shows few signs of degeneration and seems to play an important role in maintaining a residual cerebellar function in Lc/+. We asked whether the DCN in Lc/+ develop cellular adaptations allowing them to cope with the loss of GABAergic PC input. Using whole-cell patch-clamp recordings, we measured inhibitory postsynaptic currents from DCN of Lc/+ and wild-type mice (WT). In experiments on phenotypically striking Lc/+ studied well after the onset of the PC degeneration, we found enlarged average synaptic conductances (g_syn) compared with WT. We next investigated postnatal mice before and after the onset of PC death. In younger animals postnatal day (p) 13, no difference was found in g_syn between the two groups. At p14, g_syn in Lc/+ showed an increase, while those in WT stayed on the level found in younger animals. A peak-scaled nonstationary fluctuation analysis suggests that an increase in the average number of channels open at peak is the basis for the change in g_syn. The changes in g_syn, suitable to increase the efficacy of GABAergic transmission, occur in close temporal relationship to PC death and, thus, may reflect a functional adaptation to the loss of the DCN's main GABAergic afferents.

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