Rescuing neurons from trans-synaptic degeneration after brain damage: helpful, harmful, or neutral in recovery of function?

Abstract

Certain instances of neuronal degeneration secondary to brain damage might be functionally beneficial, and steps taken to protect against such degeneration may adversely affect behavioural outcome. After unilateral damage to the intrinsic neurons of the striatum, which includes GABAergic striatonigral projections, delayed trans-synaptic degeneration occurs in the ipsilateral substantia nigra pars reticulata (SNr). This degeneration was prevented by a 2-week regimen of muscimol delivered intraventricularly via osmotic minipumps. Muscimol is a direct-acting GABA agonist that presumably substituted for the absent GABA at the interface between the degenerating striatonigral GABAergic terminals and the GABAergic receptors located on SNr neurons. Sensorimotor asymmetry tests sensitive to unilateral striatal damage were carried out for 4 weeks to determine the functional consequences of the sparing of SNr neurons. Recovery of function was not improved. Instead, tactile extinction and hemiplegia were exaggerated in the contralateral forelimb. Other impairments were unaffected by the muscimol. The experiment was repeated using diazepam, rather than muscimol, to address the possibility that the disruptive effects of muscimol might reflect a more general disruptive influence on recovery processes. Diazepam, which has been shown in our lab to disrupt recovery of function after cortical lesions and to potentiate lesion-associated atrophy in remote subcortical structures, is an indirect-acting GABAergic agonist that requires GABA for its mechanism of action. Because GABAergic terminals at the SNr were destroyed, diazepam (as expected) failed to prevent SNr degeneration. Although diazepam presumably enhanced GABAergic synaptic activity in other brain regions, diazepam had no significant effect on postoperative behavioural function. Apparently, in the first experiment, the prevention of SNr degeneration per se was instrumental in the detrimental effects of muscimol. The rescued SNr neurons may have contributed to dysfunction because they lacked inhibitory GABAergic control. Transsynaptic degeneration secondary to brain damage was discussed as it might relate to release phenomena and their treatment by surgery or transmitter blocking agents in the clinical literature.