Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks
Introduction
Calcium (Ca2+) is an ubiquitous signal transduction molecule, active in a diverse range of cellular functions in the brain including the regulation of neuronal excitability, neurotransmitter release and gene transcription (Berridge, 1998). Many studies have revealed that Ca2+ has an integral role in memory processing (Bauer et al., 2002, Blackwell and Alkon, 1999, Deyo et al., 1992, Gibbs et al., 1979, Quevedo et al., 1998, Woodside et al., 2004). A vital role of Ca2+ can also be identified in long-term potentiation (LTP) and long-term depression (LTD), the putative cellular correlates of learning and memory (Bliss and Collingridge, 1993, Cavazzini et al., 2005, Lynch, 2004).
The capacity of Ca2+ to regulate cellular functions is dependent on levels in the cytosol. Intracellular Ca2+ levels can be raised by Ca2+ influx from the extracellular environment or through release from intracellular stores. The mechanisms of Ca2+ influx though plasma membrane channels are well established (Catterall, 2000). Ca2+ can also be released from intracellular stores in the endoplasmic reticulum upon activation of either ryanodine receptors (RyRs) or inositol (1,4,5)-trisphosphate (IP3) receptors (IP3Rs; Berridge, 2002, Meldolesi, 2001), but less is known about the role of such stores in memory processing. Nevertheless, a number of studies using both genetic knockout techniques and pharmacological methods have demonstrated that RyR activation contributes to LTP and LTD (Balschun et al., 1999, Futatsugi et al., 1999, O’Mara et al., 1995, Obenaus et al., 1989, Reyes and Stanton, 1996, Wang et al., 1996). In particular, RyRs appear to be involved in LTP1, a form of LTP induced by weak stimulation (Raymond and Redman, 2002, Raymond and Redman, 2006). Several behavioural studies have also demonstrated that the inhibition of RyRs impairs retention for spatial (Ohnuki & Nomura, 1996) and discrimination avoidance learning (Edwards and Rickard, 2006, Salinska et al., 2001). In addition, mice with genetic knockout of RyR subtype 3 also display deficits for contextual fear conditioning and spatial memory (Balschun et al., 1999, Kouzu et al., 2000).
IP3R-dependent calcium stores have received much less attention with respect to their role in memory processing. Interestingly, inhibition studies with the drug Xestospongin C (5 μM) suggest that IP3Rs appear to underlie LTP2, a translation-dependent, but transcription-independent form of LTP induced by moderate stimulation (Raymond, 2007, Raymond and Redman, 2002, Raymond and Redman, 2006). Behavioural studies have tended to investigate the receptors or enzymes that lead to IP3 production rather than via direct blockade of IP3Rs. As such only broad statements about the possible role of IP3Rs in memory processing can be made. For example, group I metabotropic glutamate receptors (mGluRs), which include subtype 1 (mGluR1) and 5 (mGluR5), are coupled to the enzyme phospholipase C (Pin & Duvoisin, 1995). Stimulation of group I mGluRs leads to the formation of IP3 and diacylglycerol (Hermans & Challiss, 2001), and in turn intracellular Ca2+ release (Cui et al., 2007, Kawabata et al., 1996, Kawabata et al., 1998, Power and Sah, 2007). There is a substantial body of evidence supporting a role for group I mGluRs in synaptic plasticity (Anwyl, 1999, Bashir et al., 1993, Ugolini et al., 1997, Volk et al., 2006, Yang et al., 1998) and long-term memory processing (Aiba et al., 1994, Balschun and Wetzel, 2002, Conquet et al., 1994, Riedel et al., 2003, Simonyi et al., 2005, Simonyi et al., 2007), and by broad inference IP3Rs. Interestingly, the retention loss produced by group I mGluR inhibition is consistent with the findings of Buckley and Caldwell, 2004, Weeber and Caldwell, 2004 in which phospholipase C activity was observed in the hippocampus and medial frontal cortex of rats during long-term memory formation of a fear conditioning task. Nevertheless, these findings provide only limited and indirect support for a role for IP3Rs in memory processing.
The present study sought to directly investigate the activation of IP3Rs in memory processing using a single-trial discrimination avoidance task developed for the young chick. This task has several advantages for studying the role of IP3Rs in memory formation. The task is considered to be ecologically valid and is temporally precise (Gibbs & Ng, 1977). In addition, previous studies using this task have yielded relevant findings related to intracellular Ca2+ release. For example, inhibition of RyR-dependent intracellular Ca2+ release with dantrolene (5 mM, ic) resulted in a persistent retention loss from 40 min post-training (Edwards & Rickard, 2006). In addition, Rickard and Ng (1995) demonstrated that 500 μM (RS)-α-methyl-4-carboxyphenylglycine (MCPG), a non-specific group I mGluR antagonist, administered intracranially 5 min post-training, impaired retention during long-term memory formation from 90 min post-training. In a non-discrimination variant of this task, Salinska (2006) demonstrated that the inhibition of mGluR5 using 8 mM (ic) 2-methyl-6-(phenyl)-pirydyne (MPEP), administered immediately post-training, resulted in an impairment of retention evident from 15 min post-training. Given that group I mGluRs are likely to activate IP3Rs, but that mGluR5 inhibition does not coincide with long-term memory, the current study explored the possibility that memory processing requires mGluR1-activated Ca2+ release from IP3Rs.
Section snippets
Animals
Each week, day-old white-Leghorn × black-Australorp chicks were obtained from a local hatchery. Upon arrival, chicks were allocated randomly into two batches, those to be used in experiments that day and those that were to be used the following day. Chicks for the following day’s experiments were housed in a purpose-built brooder (2.5 × 1.5 m). Crushed poultry food and water were supplied ad libitum to chicks housed in the brooder with heating maintained at 30–38 °C beneath four suspended heat lamps.
Dose response study for JNJ16259685
Various concentrations of JNJ16259685 ranging from 0.1 to 500 nM or the vehicle, were administered immediately (within 10 s) after the training trial. This range was based upon the work of Lavreysen et al. (2004) and a broad concentration range was chosen as JNJ16259685 had not been used with this task previously. Retention was tested at 120 min post-training, a time at which the long-term memory stage for this task has been well-established (Gibbs & Ng, 1977).
JNJ16259685 resulted in a
Discussion
The current study demonstrated that mGluR1 or IP3R inhibition yielded a persistent memory loss from 90 min post-training, some 30 min into the protein synthesis-dependent long-term memory stage. At a broad level, these findings implicate intracellular Ca2+ release from the IP3R store in memory processing. More specifically, the temporal consistency in retention loss following mGluR1 and IP3R inhibition suggests that IP3R-dependent intracellular Ca2+ may be released following the activation of
Acknowledgments
We gratefully acknowledge the support of E/Prof. K.T. Ng and the technical assistance of Ms E. Hartley.
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2013, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In particular, SK channels can be activated by Ca2+ transients through NMDARs (Faber and Sah, 2007; Morikawa et al., 2000; Ngo-Anh et al., 2005), therefore, NMDARs are another potential Ca2+ source for SK channel activation in memory formation. Both NMDARs and IP3Rs are implicated during the LTM stage, consistent with when SK channels are required for memory formation (Baker et al., 2008, 2011a; Rickard et al., 1994b). It is therefore difficult to be conclusive regarding the activation source of SK channels in this avian model of memory from the present correlational evidence.
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Intracellular calcium chelation and pharmacological SERCA inhibition of Ca <sup>2+</sup> pump in the insular cortex differentially affect taste aversive memory formation and retrieval
2011, Neurobiology of Learning and MemoryCitation Excerpt :Furthermore, intraperitoneal administration of BAPTA-AM before Morris water maze training significantly improved the acquisition of spatial learning in aged animals, but did not significantly affect the performance of young rats (Tonkikh et al., 2006). In agreement with these findings, several reports have demonstrated that calcium mobilized from intracellular stores is associated with a variety of learning and memory tasks (Baker, Edwards, & Rickard, 2008; Salinska, Bourne, & Rose, 2001; Simonyi et al., 2005). Specifically, during taste learning tasks, there is evidence that memory formation is partly initiated by acetylcholine interacting through the cortical muscarinic receptor coupled to G proteins that activate phospholipase C, leading to the activation of protein kinase C (PKC) (Núñez-Jaramillo, Delint-Ramirez, & Bermudez-Rattoni, 2007; Sacchetti & Bielavska, 1998; Yasoshima & Yamamoto, 1997) and the release of calcium from IP3R-associated intracellular stores.
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