A Cortical Substrate for Parkinsonism: A Personal Journey

We first started thinking that cortex must be important in Parkinson’s disease when Alan R. Crossman did some experiments in rats, showing transient reductions in 6-hydroxydopamineinduced spontaneous turning behavior after cortical lesions [1]. The experiments were elegant, but the lesions were large and did not block the turning, suggesting a kind of competition rather than a causal influence of cortex in the turning behavior. Similar conclusions plagued the many attempts to decide which of the brainstem pathways were the substrate of the turning behavior that followed the destruction of dopamine cells unilaterally, for review see, Arbuthnott and Wright [2]. However, as we finished a study of the anatomy of the basal ganglia [3] we concluded that the final output from the striatum came through the output nuclei of the basal ganglia: the globus pallidus pars interna (entopeduncular nucleus in rodents) and the substantia nigra pars reticulata, to a small nucleus in the ventral thalamus (ventromedial -VMin the rat). Tracing the output from that nucleus brought us back to layer 1 of the cortex, close to where the search started in layer V [3]. This result had the basal ganglia appearing to be a loop ‘linking’ layer 5 to the superficial level of the cortex. Not a very likely scenario, nevertheless it did prepare us to look for an involvement of cortex in the consequences of dopamine destruction. Furthermore, the evidence was already there, the striatal spiny projection neurons (SPNs) that carried the first stage of the basal ganglia output, have cortical synapses on the spines [4]. When we studied the electron microscopic (EM) anatomy of the striatum without dopamine, there were obvious differences in those SPN spines [5-7]. There were fewer of them: we counted them stereologically in serial EM sections and found statistically fewer spines when the dopamine had been removed. As the theory about the differences in the two output pathways from the striatum developed, we started a long series of experiments where we identified the cells on which the spines were counted. By then, we were not alone and the final publication brought together the laboratories of Susan R. Sesack, Ariel Y. Deutch, Jim D. Surmeier, and ourselves [8]. It may be that we missed some dopamine D1 cells that were also denuded of spines [9], but the major effect was robust across all our studies. Therefore, damage to the dopamine input to the striatum, somehow spread to the cortical synapses on the spines of the SPNs. We did most of the work on rats but we also checked that the effect occurred in Parkinsonian patients. In fact, in post mortem human brain the effects were even more marked, with a 27% reduction in spine numbers compared with the 15% in the rats [10].