Brief Report
Different time course for the memory facilitating effect of bicuculline in hippocampus, entorhinal cortex, and posterior parietal cortex of rats

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Abstract

Several lines of evidence indicate that γ-aminobutyric acid (GABA) type A (GABAA) receptors regulate memory consolidation. Here we studied the effect on consolidation of the selective antagonist of GABAA receptors, bicuculline, given into several regions of the cortex at different times after one-trial step-down inhibitory avoidance (0.5 mA, 2-s footshock). Rats were bilaterally implanted with cannulae aimed at the CA1 region of the dorsal hippocampus, entorhinal cortex or posterior parietal cortex, three areas known to be involved in the memory consolidation of this task. At different times after training, bicuculline (0.5 μg/side) was infused into the above mentioned structures. Bicuculline increased memory retention when administered either immediately or 1.5 h after training into CA1, and both immediately and 3 h after training in the entorhinal or parietal cortex. Thus, in agreement with previous findings using other drugs, the response was biphasic in these latter structures. This suggests that GABAergic mechanisms normally downregulate, memory processing by inhibiting on-going activities necessary for consolidation at the times in which bicuculline was effective in each structure. Based on previous findings, in the hippocampus, such activity involves a number of receptors and signaling pathways in the first 1.5 h after training. In the entorhinal and parietal cortex memory-related activities include the participation of protein kinase A and extracellularly regulated kinase (ERK) twice, right after training and then again 3 h later.

Introduction

Memory is not formed immediately after training; it undergoes a process of consolidation that lasts at least several hours (Ardenghi et al., 1997; Bernabeu et al., 1997; Bonini et al., 2003; Rossato et al., 2004) and involves a series of parallel and sequential biochemical events in the hippocampus and elsewhere. These processes include the selective activation of receptors to glutamate and other transmitters, signaling pathways, gene expression, and protein synthesis. The process occurs in at least two “waves,” the first shortly after training and the second three or more hours later (Igaz, Vianna, Medina, & Izquierdo, 2002; Matthies, 1989; Rose, 1995) and is not over in less than 6 h (Izquierdo & Medina, 1997; Rossato et al., 2004). Indeed, several authors think that it might last much longer: days or (in rodents) even weeks (see Squire, 1992). This lengthy process is believed to underlie the consolidation of memories into a stable state (Izquierdo & Medina, 1997; McGaugh, 2000).

Further, memory is certainly not formed or consolidated in just one place (Izquierdo et al., 1992). Abundant evidence indicates that the consolidation of a task as simple as one-trial inhibitory avoidance learning involves the CA1 area of the hippocampus, the entorhinal cortex, the posterior parietal cortex (Ardenghi et al., 1997; Izquierdo et al., 1997; Rossato et al., 2004), and other areas (Lorenzini, Baldi, Bucherelli, Sacchetti, & Tassoni, 1996), among which the basolateral amygdala (Bonini et al., 2003; Cahill & McGaugh, 1998; Rossato et al., 2004) and the medial septum (Izquierdo et al., 1992) play important modulatory roles. Thus, Brioni (1993) coined the expression “the multiple consolidation of memory”. The areas involved in consolidation enter into action at different times, as measured by the effect of glutamate receptors antagonists (Bonini et al., 2003; Rossato et al., 2004), inhibitors of protein kinase A, drugs that modulate the activity of that enzyme (Ardenghi et al., 1997), inhibitors of the extracellularly regulated protein kinase chain (ERK) (Rossato et al., 2004) and the GABAA receptor agonist, muscimol (Izquierdo et al., 1992, Izquierdo et al., 1997; Rossato et al., 2004). The sequential entry into action of these variables, as well as the fact that several of them do so biphasically (Bernabeu et al., 1997; Igaz et al., 2002; Matthies, 1989; Rose, 1995), indicate that the biochemical processes crucial for consolidation are different in each of these brain sites (Izquierdo & Medina, 1997; Rossato et al., 2004), which renders simplistic, single-brain site or single-process explanations untenable (Izquierdo et al., 2002).

The early events of the biochemical cascade of memory are inhibited by γ-aminobutyric acid (GABA) type A receptors (Brioni, 1993). GABA is the main inhibitory neurotransmitter in the central nervous system and is known to be involved in a variety of physiological functions (Roberts, 1986). The characteristic response of the post-synaptic neuron to GABAA receptor activation is electrical inhibition mediated by an increase in chloride conductance (McBurney & Barker, 1978). Fast synaptic inhibition in the brain is largely mediated by GABAA receptors, which are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are implicated in several diseases including epilepsy, anxiety, depression, and substance abuse (Kittler, McAinsh, & Moss, 2002). Furthermore, pharmacological studies utilizing the inhibitory avoidance task have demonstrated that post-training injections of GABAergic compounds modulate memory storage (Hatfield, Spanis, & McGaugh, 1999). In general, GABAA agonists, such as muscimol, impair retention, while antagonists enhance it. These findings provide strong support for the view that GABAA receptors modulate post-training processes underlying memory consolidation (Ammassari-Teule, Pavone, Castellano, & McGaugh, 1991; Brioni & McGaugh, 1988; Castellano, Brioni, & McGaugh, 1990; Castellano & McGaugh, 1990).

Previous studies have reported that the GABAA receptor antagonist bicuculline causes retrograde facilitation for aversively motivated learning when given systemically (Brioni & McGaugh, 1988) or into the amygdala (Brioni, Nagahara, & McGaugh, 1989). Here we study the effect of bicuculline given into the CA1 region of the dorsal hippocampus, the entorhinal cortex, and the posterior parietal cortex on memory consolidation. These three brain areas are interconnected via the entorhinal cortex by both afferent and efferent pathways (Hyman, Van Hoesen, & Damasio, 1990) and all of them have been shown to be actively involved in numerous forms of memory (Squire, 1992), including, as said, that of one-trial avoidance.

Bicuculline was administered at different times after training (Ardenghi et al., 1997; Bonini et al., 2003; Rossato et al., 2004). This was in order to ascertain whether the intervention of GABAA receptors in consolidation (Brioni, 1993; Izquierdo et al., 1992) occurs also in “waves,” as is the case of dopaminergic-D1, β-noradrenergic, serotonin-1A and different types of glutamate receptors and signaling pathways (Ardenghi et al., 1997; Rossato et al., 2004). In addition, we thought it useful to find out whether the time course of the action of bicuculline, if any, was coincident with that previously reported for muscimol given into the same brain structures (i.e., Izquierdo et al., 1997; Rossato et al., 2004). The action of an agonist determines whether the system under scrutiny is sensible to stimulation of that receptor, whereas that of an antagonist gives clues that the system is physiologically active in the variable under measure; in this case, memory formation (Ardenghi et al., 1997).

Section snippets

Methods

A total of 324 male Wistar rats (2.5–3.5 months) were used. They were housed five to a cage and maintained under a 12 h light/dark cycle (lights on at 7:00 h) at a constant temperature of 23 °C with water and food ad libitum.

Rats were bilaterally implanted under deep thionembutal anesthesia (30 mg/kg, ip) with 27-gauge guide cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus (AP 4.2 mm; ML 3.0 mm; and DV 1.3 mm), entorhinal cortex (AP 6.7 mm; ML 5.0 mm; and DV 3.3 mm) or posterior

Results

Fig. 2 shows the effect of bicuculline given into the CA1 area of the dorsal hippocampus, the entorhinal cortex or the posterior parietal cortex at different post-training times on inhibitory avoidance long-term memory retention as measured 24 h after training. Bicuculline caused memory facilitation when infused into CA1 either immediately or 1.5 h post-training, but not at intermediate or later times. Bicuculline also caused facilitation when given into the entorhinal or parietal cortex at two

Discussion

The present findings indicate that retention of an inhibitory avoidance response is enhanced by post-training infusions of the GABAergic antagonist bicuculline into CA1, entorhinal cortex, and posterior parietal cortex. This adds to previous demonstrations that the three areas are involved in memory consolidation of this task (Ardenghi et al., 1997; Bonini et al., 2003; Izquierdo et al., 1997; Lorenzini et al., 1996; Rossato et al., 2004). In addition, it suggests that inhibition of on-going

Acknowledgments

This work was supported by grants from CNPq, CAPES, and FAPERGS, Brazil.

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