Immunotoxins

Cholinergic Neurotoxins

The selective targeting of cholinergic neurons for a long time relied on the selective placement of excitotoxins into the circumscribed cell body nuclei in the medial septum and the NBM. This achieved effective lesions of the target neurons and extensive cholinergic deafferentation of the targets of cholinergic projections in the cortex and hippocampus, respectively, but could never be demonstrated to be specific; co-localized non-cholinergic neurons and parallel projections were typically equally affected (e.g., damage to the parvalbumin-positive ► GABA neurons of the medial septum projecting in parallel to the hippocampus). A claim was made for cholinergic selectivity for the ethyl-choline mustard axiridinium ion, AF-64A, but this has not been well supported. In the hands of most people, AF-64A produces cavitation at the site of injection and extensive nonspecific lesions. Greater specificity has subsequently been demonstrated for the immunotoxin, 192-IgG ► saporin.

Immunotoxins

Following a similar logic to the familiar neuroanatomical use of antibodies to label specific target molecules on cells in a range of sensitive immunohistochemistry techniques, immunotoxins involve conjugating an immunoglobulin antibody (or immunoglobulin fragment) to target cell surface receptors or channels with a cytotoxin that will then induce death of the target cell. The trick is to select targets such as neurotrophic factor receptors, which will internalize the ligand, thereby allowing the toxin to be transported into the cell for intracellular concentration, often with active transport back to the cell body where its primary toxic action takes effect. A range of antibody fragments and cytotoxins have now been developed for a range of application, the first of which to receive major attention was 192-IgG saporin.

192-IgG Saporin

192-IgG saporin was the first used and most extensively explored of the burgeoning range of immunotoxins. The 192-IgG immunoglobulin recognizes the p75 low affinity NGF receptor which is widely expressed on cholinergic neurons in the forebrain. After central injection, 192-IgG saporin binds to the NGF receptor, achieving selective internalization preferentially in cholinergic neurons, retrograde transport of the cytotoxin saporin to the cell body and consequent death of the cell. Although the preparation and stability of the toxin and precise parameters of injection are important, 192-IgG saporin has proved the most successful technique for selective lesion of septal and basal forebrain neurons sparing co-localized cells, and has been widely used to confirm that many of the electrophys-iological and behavioral changes in learning and memory function associated with excitotoxic lesions of the medial septum and NBM are indeed attributable to the selective depletion of the cholinergic innervations of the hippocampus and cortex respectively.

Other Immunotoxins

More recently, other immunotoxins have been developed using a similar conjugate strategy to develop tools for simple and effective lesion of NA neurons by targeting the synthetic enzyme dopamine-B-hydroxylase; DA neurons by targeting the ► DA transporter; striatal neurons by targeting the substance P receptor; and selective lesions of basal forebrain neurons receiving glutamatergic projections by conjugating saporin to the NMDA receptor. Indeed, the selectivity provided by immunotoxins allows a variety of previously intractable experimental issues to be addressed, such as the relative contributions of striosome and matrix compartments of the striatum by targeting the striosome projection neurons with a saporin-antibody complex recognizing the ► m-opiate receptor.

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