Chetan C. Gandhi

Injection of IgG 192-saporin into the medial septum produces cholinergic hypofunction and dose-dependent working memory deficits

192-IgG saporin is an anti-neuronal immunotoxin that combines the 192 monoclonal antibody to the p75 neurotrophin receptor found on terminals and cell bodies of neurons in the cholinergic basal forebrain with the ribosome-inactivating protein saporin. Injection of 100, 237.5 or 375 ng of 192-saporin into the medial septum produced dose-related deficits in a variable-delay radial-arm maze task. 192-saporin decreased the number of correct choices and increased the number of errors in the delayed non-match to sample task. These deficits persisted throughout training and were most evident in the 375 ng group. The behavioral deficits were associated with dose-dependent decreases in pre-synaptic cholinergic parameters (ie., high affinity choline uptake) in the terminal fields of the medial septum (hippocampus, cingulate, entorhinal cortex). Choline uptake was not affected in the frontal cortex or the striatum; structures not innervated by the septum. There were no changes in regional concentrations of dopamine, serotonin, or their metabolites. Site-specific injection of IgG 192-saporin is a useful approach to explore the functions of the cholinergic basal forebrain and to model diseases of cholinergic hypofunction such as Alzheimers disease.

Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus.

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABA(A) receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 microg), or zolpidem (4, 8, or 12 microg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 microg). However, intraseptal injection of 8 microg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway.

Reversible inactivation of the medial septum or nucleus basalis impairs working memory in rats : A dissociation of memory and performance

Lidocaine-induced inactivation of the medial septum immediately after training or prior to testing in a delay radial-arm maze task produced deficits in spatial working memory that reflected impaired acquisition of the task. Injection of lidocaine into the nucleus basalis magnocellularis produced a profile of behavioral changes that indicated that temporary inactivation of this structure impaired the behavioral expression of information already stored in working memory. This appears to reflect an impairment in processes that are required for performance (i.e., attention, motivation, sensorimotor function) of the task but not for retrieval of stored information. Site-specific inactivation of the basal forebrain should help to reveal the involvement of its component structures in different aspects of cognitive function.

Synaptic efficacy is commonly regulated within a nervous system and predicts individual differences in learning

The hypothesis that an individuals capacity for learning might be predicted or influenced by basal levels of synaptic efficacy has eluded empirical tests, owing in part to the inability to compare between animals single identified synaptic responses in the mammalian brain. To overcome this limitation, we have focused our analysis on the invertebrate Hermissenda, whose nervous system is composed of identifiable cells and synaptic interactions. Hermissenda were exposed to paired presentations of light and rotation such that the light came to elicit a learned defensive motor response. An animals rate of learning was strongly correlated with the amplitude of the synaptic potential evoked in that animals visual (light sensitive) receptors in response to stimulation of presynaptic vestibular (rotation sensitive) hair cells. In naive animals, strong correlations between the amplitude of both inhibitory and excitatory synaptic potentials were observed between synapses distributed throughout an animals nervous system, and this conservation of synaptic efficacy was largely attributable to a common influence on transmitter release. These observations suggest that basal synaptic efficacy may be uniformly regulated throughout a nervous system, and provide direct evidence that the basal efficacy of synaptic transmission predicts, and possibly contributes to, individual differences between animals in their capacity to learn.