Targeting Topics 00q4

Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin.

Gandhi CC, Kelly1 RM, Wiley RG, Walsh TJ.

Behav Brain Res 109(1):37-47, 2000. PMID: 10699656

The cerebellum has been associated with the control of motor activity and voluntary movements. Recent data have shown the cerebellum may also play a role in “higher order” processes such as learning, language, and cognition. Using 2 μg OX7-SAP (Catalog #IT-02) by i.c.v. injection, Gandhi et al. selectively eliminated Purkinje cells in rat cerebellum in order to examine the ability of treated animals to complete a water maze task. Elimination of these cells significantly impaired the ability of the rats to complete the task, suggesting the cerebellum is involved in learning.

Ectopic noradrenergic hyperinnervation does not functionally compensate for neonatal forebrain acetylcholine lesion.

Pappas BA, Nguyen T, Brownlee B, Tanasoiu D, Fortin T, Sherren N.

Brain Res 867(1-2):90-99, 2000. PMID: 10837801

Removal of cholinergic forebrain neurons in the neonatal rat causes an ingrowth of hippocampal material to the affected area. The behavioral effect of this treatment increases working, but not reference memory errors on the radial arm maze. Pappas et al. used 300 ng 192-Saporin (Catalog #IT-01) by i.c.v. injection to lesion the forebrain of 1- to 3-day old rats coupled with a 6-OHDA lesion to remove hippocampal ingrowths in order to investigate whether these neurons can compensate for cholinergic function in memory. Their results indicate noradrenergic neurons from the hippocampus do not functionally compensate for loss of CBF neurons even though losses of these neurons did not drastically affect the behavior of these animals.

NGF-mediated alteration of NF-kappaB binding activity after partial immunolesions to rat cholinergic basal forebrain neurons.

Gu Z, Toliver-Kinsky T, Glasgow J, Werrbach-Perez K, Perez-Polo JR.

Int J Dev Neurosci 18(4-5):455-468, 2000. PMID: 10817930

After injecting 1.3 μg 192-Saporin (Catalog #IT-01) into the lateral ventricle of rat brain, followed by infusion of NGF antibody, Gu et al. report changes in the activity of the transcription factor NF-κB. Aged rodent brains show an increase in NF-κB activity. This model creates a tool to investigate decreased cholinergic function that is often associated with memory loss and cognitive deficits in the elderly and particularly in patients with Alzheimer’s disease.

Sustained visual attention performance-associated prefrontal neuronal activity: evidence for cholinergic modulation.

Gill TM, Sarter M, Givens B.

J Neurosci 20(12):4745-4757, 2000. PMID: 10844044

Preliminary evidence suggests that demands on attention levels are associated with changes in levels of cortical acetylcholine. Gill et al. used.05 μg 192-Saporin (Catalog #IT-01) by intracortical infusion to demonstrate the role cholinergic neurons play in the ability of rats to pay attention. The researchers monitored medial prefrontal cortex (MPC) activity in the rat brain before and after elimination of cholinergic neurons with 192-Saporin. The results suggest that the cholinergic inputs to the MPC influence the increases of neuronal activity associated with paying attention.

Preferential destruction of cerebellar Purkinje cells by OX7-saporin.

Angner RT, Kelly RM, Wiley RG, Walsh TJ, Reuhl KR.

Neurotoxicology 21(3):395-403, 2000. PMID: 10894129

Purkinje cells function as inhibitors and are the sole output of the cerebellar cortex. Angner et al. eliminate these cells in rats with 1-2 μg OX7-SAP (Catalog #IT-02), an immunotoxin that binds the Thy 1.1 antigen. The treated rats show effects of loss of inhibitory control, including a time-dependent increase in motor activity and decreased motor coordination.

Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter.

Schroeter S, Apparsundaram S, Wiley RG, Miner LH, Sesack SR, Blakely RD.

J Comp Neurol 420(2):211-232, 2000. PMID: 10753308

Norepinephrine transporters are involved in the response to multiple antidepressants and psychostimulants, but the expression of these proteins has not yet been characterized in the central nervous system. Schroeter et al. used an antibody to a cytoplasmic epitope of norepinephrine transporters to map the transporters to noradrenergic neuronal somata, axons, and dendrites. To verify the specificity of the antibody the researchers injected 10 μg of anti-DBH- SAP (Catalog #IT-03) in the left lateral ventricle of rats to destroy the noradrenergic neurons, confirming the specificity of the norepinephrine transporter antibody. Treatment with anti-DBH-SAP completely removed norepinephrine transporter immunoreactivity.

Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats.

Ferencz I, Leanza G, Nanobashvili A, Kokaia M, Lindvall O.

Eur J Neurosci 12(6):2107-2116, 2000. PMID: 10886350

Cholinergic mechanisms have been implicated in human epilepsy, possibly in the role of seizure suppression. Ferencz et al. used 2.5 μg 192-Saporin (Catalog #IT-01) by i.c.v. injection to investigate the effect of eliminating cholinergic projections to the hippocampal formation and cerebral cortex on the induction of epilepsy through electrical stimulation of the rat brain. The researchers used the specificity of 192-Saporin to determine that the loss of specific projections to the amygdala accelerates development of seizures. The hippocampus does not influence this process.

Repeated immunolesions display diminished stress response signal.

Gu Z, Yu J, Werrbach-Perez K, Perez-Polo JR.

Int J Dev Neurosci 18(2-3):177-183, 2000. PMID: 10715572

Cholinergic neurons in the basal forebrain are involved in neurotrophin release in general injury response although this response is impaired in the aged individual. Addition of pharmacological doses of NGF can repair this mechanism. Gu et al. used 192-Saporin (Catalog #IT-01) to model the endogenous stimulation of NGF in response to injury. They found that a one-time administration of 192-Saporin was more effective than chronic repeated administrations for inducing an increase in NGF levels. These results indicate that chronic lesions may cause a desensitization that differs from the acute toxic model.

Cholinergic excitation of septohippocampal GABA but not cholinergic neurons: implications for learning and memory.

Wu M, Shanabrough M, Leranth C, Alreja M.

J Neurosci 20(10):3900-3908, 2000. PMID: 10804229

It has long been assumed that the drug- induced enhancement of learning and memory in both young and aged rats was accomplished through a cholinergic pathway in the hippocampus. Wu et al. used a fluorescent labeling molecule, 192-IgG conjugated to Cy3 (Custom Service from ATS) to visualize these neurons. They found that the effects of cognition-enhancing drugs are not facilitated through action on cholinergic neurons. Instead, activation of GABA neurons is implicated in this model.

Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.

Stowell JR, Berntson GG, Sarter M.

Psychopharmacology (Berl) 150(2):141-149, 2000. PMID: 10907667

The benzodiazepine receptor (BR) is involved in anxiety. It has been hypothesized that cholinergic projections from the CBF are necessary for modulation of the BR by agonists and inverse agonists. Stowell et al. directly injected 0.18 μg 192-Saporin (Cat #IT- 01) into each hemisphere of the CBF in adult rats. The treated rats had altered responses to external stimuli during an operant conditioned task. These results indicate that the CBF plays an important role in response to fear and anxiety- related stimuli. This system may also mediate the actions of BR ligands.

Intracerebroventricular infusion of CHO5, a rat monoclonal antibody directed against mouse low-affinity nerve growth factor receptor (p75NTR), specifically labels basal forebrain cholinergic neurons in mouse brain.

Rossner S, Schliebs R, Bigl V.

Metab Brain Dis 15(1):17-27, 2000. PMID: 10885538

192-Saporin (Catalog #IT-01) has long been a useful tool for neurobiological research in the rat. For various reasons, many researchers want to perform the same studies in the mouse but have been prevented from doing so by the lack of a suitable antibody against the mouse p75NTR. Rossner et al. describe a rat monoclonal antibody against the mouse p75NTR (Catalog #AB-N02) that demonstrates co-localization of p75NTR and ChAT, and also co-localization of p75NTR and TrkA in the mouse basal forebrain. Internalization and retrograde transport of this antibody in cholinergic basal forebrain neurons is also shown. This evidence indicates that the anti- mouse p75NTR will be effective for use as an immunotoxin.