DHPG activation of group 1 mGluRs in BLA enhances fear conditioning

Group 1 metabotropic glutamate receptors are known to play an important role in both synaptic plasticity and memory. We show that activating these receptors prior to fear conditioning by infusing the group 1 mGluR agonist, (R.S.)-3,5-dihydroxyphenylglycine (DHPG), into the basolateral region of the amygdala (BLA) of adult Sprague–Dawley rats enhances freezing normally supported by a weak footshock. This effect of DHPG was blocked when it was co-infused with either the general group 1 mGluR1 antagonist, (R,S)-1-aminoindan-1,5 dicarboxylic acid (AIDA), or with the selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). These results support previous findings by Rodrigues and colleagues that mGluR5s in the lateral region of the amygdala make an import contribution to fear conditioning. More importantly, they support the general ideas embedded in the concept of metaplasticity, as per Abraham, and the synaptic-tagging hypothesis per Frey and Morris—that the processes that specify the content of experience can be experimentally separated from those needed to acquire the memory.The last decade has seen an increased appreciation of the view that the plasticity state of neurons—their ability to be modified by experience—is not fixed. Instead, the effect of experience depends on the physiological or biochemical state of the neurons or synapses that receive and store information contained in the experience, and this state is variable. This perspective is captured by the concept called “metaplasticity” (Abraham and Bear 1996; Abraham and Tate 1997; Abraham 2008), which recognizes that prior events can change the general plasticity or modifiability of neurons and synapses that will potentially store information contained in a subsequent target experience. This idea is also embedded in the synaptic-tagging hypothesis (Frey and Morris 1997, 1998) that will be described in some detail in the Discussion section. This view is important because it recognizes that the processes that specify the content of experience can be experimentally separated from those that are needed to store the memory for the experience.As reviewed by Abraham (2008), the range of prior events that can potentially determine a neuron''s state of plasticity is quite large and can be mediated by their effects on many components of the machinery that supports changes in synaptic strength. They include modification in NMDA-receptor function, AMPA-receptor trafficking, neuronal excitability, and epigenetic modifications.One way that the potential for plasticity can be altered is by activation of group 1 metabotropic glutamate receptors (mGluR1s and mGlur5s) (Abraham 2008). A number of reports based on the in vitro long-term potentiation (LTP) methodology suggest that activating this class of receptors prior to the delivery of a relatively weak inducing stimulus can transform a normally short-lasting form of LTP into a more persistent form (Cohen and Abraham 1996; Cohen et al. 1998; Raymond et al. 2000). For example, an infusion of (R.S.)-3,5-dihydroxyphenylglycine (DHPG), a group 1 mGluR agonist, into the bathing medium 30 min prior to the delivery of a weak inducing stimulus can significantly enhance the persistence of the resulting LTP, while having no effect on the baseline response (Cohen et al. 1998; Raymond et al. 2000). This effect of DHPG, however, is blocked (Raymond et al. 2000) when its administration is accompanied by an infusion of the group 1 mGluR antagonist, (R,S)-1-aminoindan-1,5 dicarboxylic acid (AIDA).Group 1 mGluRs also have been implicated in fear conditioning. For example, Rodrigues et al. (2002) reported that one subtype, mGluR5, is localized in dendrites and spines in neurons in the lateral nucleus of the amygdala, and fear conditioning can be significantly impaired if the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), is infused into the lateral nucleus prior to conditioning.These findings, from the studies of synaptic plasticity and fear conditioning, provide the empirical basis for the hypothesis that motivates the experiments reported here—that the plasticity potential of neurons in the amygdala that support fear conditioning can be increased by activating group 1 mGluRs prior to the conditioning experience.To evaluate this idea, we followed a strategy similar to that used to study the role of mGluRs in LTP (Cohen and Abraham 1996; Cohen et al. 1998; Raymond et al. 2000). In these in vitro LTP experiments, a relatively weak inducing stimulus was used to generate a short-lasting LTP. Infusing the group 1 agonist DHPG prior to the delivery of the inducing stimulus transformed this short-lasting LTP into a more persistent form. Their results suggest that the activation of group 1 mGluR1 receptors independently initiates processes that make an important contribution to long-lasting LTP. To apply this strategy to fear conditioning, we used a very low level of shock—one that by itself produced an almost undetectable level of conditioned fear (as measured by freezing, the innate defensive response of rodents). We then determined if the activation of group 1 mGluRs prior to the conditioning experience would transform this outcome and produce a stronger level of freezing. DPHG was infused into the basolateral region of the amygdala (BLA) to activate the mGluRs.