Role of GABA during the multiple consolidation of memory

Abstract

Alzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients i s the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA-A and GABA-B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA-A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of these drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose-and time-related, and cannot be explained by state-dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long-term potentiation (LTP); (7) GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo-hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as a multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the "multiple consolidation" process of memory storage. o 1993 WiIey-Liss, Inc.

Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval

“…The results, when put together, suggest a multicenter GABA A modulation of retrieval reminiscent of the multicenter GABA A modulation of consolidation suggested 20 years ago by Brioni (27). GABA is the main inhibitory neurotransmitter in the brain, and its effect on GABA A receptors is mimicked by Mus.…”

Long‐term potentiation and the mechanisms of memory

“…Aniracetam., a drug that enhances some forms of memory in laboratory animals [Gamzu, 19851, increases the mean open time of AMPA ionophores [Tang et al, 19911 and interacts in a complex fashion with LTP [Lynch and Granger, 19921. Unfortunately, the effects of aniracetam or other drugs of its class (the "nootropics") on human memory and amnesia are not very encouraging [Brioni, 1993;Gamzu, 19851. The changes in glutamate receptors that occur during LTP may be reflected in changes of their binding properties, and this has been proposed to occur during memory formation [Thompson, 19911. Keller et al [ 19921 reported [Thompson, 1991;Tocco et al, 19911 have reported a selective increase of AMPA but not of NMDA receptor binding in the hippocampus of rats trained in a classical conditioning task (eye-blink conditioning) that involves this structure.…”

“…It is unlikely that drugs that act on other neu-rotransmitter systems, or just on general brain metabolism or circulation, may do more than extrinsically modulate glutamatergic or, perhaps, GABAergic transmission. The drugs currently in use belong predominantly to these types [Brioni, 1993;Gamzu, 19851. Among other drugs more recently studied, several families would appear to deserve closer examination and include modulators of NMDA receptors at the glycine site [Jones et al, 1991;Monahan et al, 19891, modulators of AMPA receptors [Lynch and Granger, 19921, agonists at the presumably modulatory nicotinic cholinergic receptors [ Brioni and Arneric, 19931, and modulators of GABAergic transmission [Brioni, 19931, including adrenal steroids and their metabolites [Dubrovsky, 19931. Many drugs that act upon modulatory mechanisms have been postulated over the years as of possible therapeutic value in human amnestic disorders and include epinephrine, ACTH, ACTH fragments, opioid receptor antagonists, etc.…”

“…In general, the drugs are studied on systems in which test drugs have been produced, creating a somewhat cyclical justification of drug activity. Thus, experimental agents are studied on animal models ofmemory, not memory disorders, and their effects are then transposed to their putative influence on memory disorders [see Brioni, 1993;Gamzu, 19851. The use of aging animals may be useful as a model for the so-called "benign amnesia" of the elderly, but not for degenerative brain diseases since aging is not necessarily synonymous with dementia [Arriagada et al, 1992;Izquierdo, 1993bl.…”

Differential effects of aging on EEG after baclofen administration

“…However, few studies have examined the relationship between the GABA B receptor and age-related changes in brain activity. Nevertheless, GABA B receptors have been implicated in memory processes [8], and GABA B receptor binding is altered in Alzheimer's disease [9,10]. Therefore, in the present study, we determined whether aging has an effect on cortical electrical activity that is associated with the GABA B receptor.…”