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The Journal of Neuroscience, July 30, 2008, 28(31):7797-7807; doi:10.1523/JNEUROSCI.1885-08.2008

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Neurobiology of Disease
Functional Convergence of Dopaminergic and Cholinergic Input Is Critical for Hippocampus-Dependent Working Memory

Liselijn A. B. Wisman,¹ Gurdal Sahin,¹ Matthew Maingay,¹ Giampiero Leanza,^2 * and Deniz Kirik^1 *

¹Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden, and ²B.R.A.I.N. Centre for Neuroscience, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy

Correspondence should be addressed to Deniz Kirik, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, SE-221 84 Lund, Sweden. Email: Deniz.Kirik{at}med.lu.se

Although Parkinson's disease is a movement disorder, in many patients cognitive dysfunction is an important clinical sign. It is not yet clear whether this is attributable solely to a decrease in dopamine levels, or whether other neurotransmitter systems might be involved as well. In the present study, the importance of the mesocorticolimbic dopamine pathway and a possible convergence with forebrain cholinergic projections to neocortex and hippocampus in the regulation of learning and memory abilities were investigated by using specific lesion paradigms in one or both systems. Lesioning of dopaminergic neurons in the ventral tegmental area resulted in an impaired performance in the reference memory task, whereas the execution of the working memory tasks appeared to be unaffected in the Morris water maze. Analysis of the swim paths revealed that the dopamine-depleted animals were capable of adapting a search strategy on a given testing day but failed to transfer this information to the next day, suggesting a deficit in information storage and/or recall. In contrast, cholinergic lesions alone were without effect in all test paradigms. However, when both dopamine and acetylcholine were depleted, animals were also impaired in the working memory task, indicating that a functional convergence of the inputs from these systems was critical for acquisition of spatial memory. Interestingly, such an additional acquisition deficit appeared only after hippocampal cholinergic depletion regardless of a concurrent disruption of basalo cortical cholinergic afferents. Thus, further analyses of cholinergic alterations may prove useful in better understanding the cognitive symptoms in Parkinson's disease.

Key words: Parkinson's disease; dopamine; acetylcholine; 6-hydroxydopamine; 192 IgG-saporin; learning and memory; water maze test; stereology; rat

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Received Feb. 24, 2008; revised June 11, 2008; accepted June 18, 2008.

Correspondence should be addressed to Deniz Kirik, Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, SE-221 84 Lund, Sweden. Email: Deniz.Kirik{at}med.lu.se

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