1. ¹Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-9157, USA
2. ²Neurology Service, Veterans Affairs Medical Center, San Diego, CA 92161, USA
3. ³Laboratory of Genetics, Salk Institute, La Jolla, CA 92037, USA
4. ⁴Division of Nephrology and Hypertension, University of California at San Diego, La Jolla, CA 92093-9157, USA

Correspondence: Donald P. Pizzo, Department of Neurosciences, University of California at San Diego, VA Medical Center MC 9151, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Fax: (858) 552-7513. E-mail: dpizzo@ucsd.edu

Received 21 June 2005; Revised 2 August 2005; Accepted 2 August 2005.

Abstract

Regulatable gene therapy systems provide a method to alter neurotransmitter levels in vivo. We developed a rodent fibroblast cell line expressing the choline acetyltransferase (ChAT) cDNA that is silenced by doxycycline (DOX) administration. The ability of the cell line to improve cognition was tested by grafting after cholinergic lesions. Ibotenic acid was injected bilaterally into the nucleus basalis of rats, which were distributed into three groups. One group received no treatment, while the second group received cortical transplants (Graft). The third group received identical grafts but was treated with DOX to turn off ChAT expression (Graft/DOX). An unlesioned group served as control. Water maze acquisition was significantly better in the Graft group compared to the Graft/DOX group, an effect also seen in the retention and spatial probe trials. However, cognitive enhancement was restricted to spatial tasks, as inhibitory avoidance or open-field activity measures were unchanged. Molecular and biochemical analyses confirmed that DOX regulated transgene transcription and ACh levels. This study demonstrates that regulatable gene therapy has therapeutic value for single-gene disorders and also provides a mechanism to deliver small molecules in a spatiotemporal pattern to delineate the role of these compounds in discrete behavioral tasks.