Introductory Review Cellscience Reviews Vol.2 No.3 ISSN 1742-8130

Role and Mechanism of the RAS Effector RIN1 in Neuronal Plasticity

Joanne M. Bliss & John Colicelli

Introduction

Neurons have a remarkable capacity to modify synaptic connections in response to past activity, a facility referred to as plasticity. These enduring changes in neuronal signaling are believed to serve as an underlying basis for memory (Bliss & Collingridge, 1993). Evidence of neuronal plasticity can be observed electrophysiologically as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are induced in brain slices by specific stimulation regimens, resulting in a strengthening or weakening, respectively, of the synaptic connections in the affected neuronal circuits (Bear & Malenka, 1994; Malenka & Bear, 2004). Alterations in both pre- and post-synaptic regions have been implicated in synaptic plasticity, with particular attention being focused on postsynaptic structures called spines and on signaling complexes associated with the postsynaptic density (PSD). Several cell processes, such as receptor trafficking (Collingridge et al., 2004; Malinow & Malenka, 2002) and cytoskeletal remodeling (Carlisle & Kennedy, 2005; Yuste & Bonhoeffer, 2001), have emerged as crucially important for organizing and reorganizing the signaling complexes that transduce action potentials into long-term changes in synaptic strength. CAMK2A (CamKIIα) and DLG4 (PSD-95) are among the specific signaling proteins known to mediate LTP postsynaptically, and their contributions to neuronal plasticity have been extensively reviewed elsewhere (Kennedy, 2000; Kennedy et al., 2005; Sheng & Kim, 2002). Attempts to understand the neuronal plasticity function of RAS proteins (HRAS, KRAS and NRAS), long studied as regulators of cell mitosis and as protooncoproteins, have led to a reexamination of downstream effector pathways. While some RAS effectors are already well established contributors to LTP and learning (Sweatt, 2004; Thomas & Huganir, 2004), other RAS effectors are just emerging as important modulators of plasticity. This review will focus on the RAS effector RIN1 and its role in neuronal plasticity.

RIN1 Regulates Multiple RAS Effector Pathways

RIN1 (RAS and RAB INteracting) was first isolated and characterized based on its ability, when overexpressed, to interfere with known RAS signaling pathways (Han & Colicelli, 1995). Through a RAS binding domain, RIN1 specifically binds to the activated GTP-bound form of RAS (Han et al., 1997, Figure 1). Subsequently, RAS binding enhances RIN1's ability to interact with the SH2 and SH3 domains of ABL family tyrosine kinases (ABL1 and ABL2) (Afar et al., 1997; Hu et al., 2005). RIN1 binding leads to activation of ABL kinases, which regulate cytoskeletal remodeling through downstream substrates such as the adaptor proteins CRK and CRKL (Hernandez et al., 2004; Woodring et al., 2003). In epithelial cells, RIN1 regulates ABL signaling and cytoskeletal remodeling in response to cell attachment and chemotactic cues (Hu et al., 2005).

Figure 1. Model of RIN1 protein-protein interactions. RIN1 is a RAS effector that modulates cytoskeletal remodeling through activation of ABL family tyrosine kinases. RIN1 also enhances RAB5-mediated endocytosis of receptor tyrosine kinases.

Additional RIN1 functions are mediated by its ability to activate the GTPase RAB5, a regulator of clathrin-dependent endocytosis and vesicular trafficking (Bucci et al., 1992; Zerial & McBride, 2001). As with most GTPases, RAB5 is active in its GTP-bound form and inactive when bound to GDP. RIN1 contains guanine nucleotide exchange factor (GEF) activity for RAB5, catalyzing the exchange of GDP for GTP and thereby promoting RAB5-mediated endocytosis of cell-surface receptors in vivo (Barbieri et al., 2003; Tall et al., 2001). In addition, RIN1 can interact with several receptor tyrosine kinases through an amino-terminal SH2 domain and this interaction is important for RIN1's ability to activate RAB5-mediated endocytosis of these receptors (Barbieri et al., 2003).

Unlike most RAS effectors, RIN1 has a rather restricted expression pattern. The highest levels of RIN1 are seen in forebrain neurons with lower levels of expression in epithelial cells and some hematopoetic cells but little, if any, expression in fibroblasts (Dhaka et al., 2003). Within the forebrain, RIN1 protein localizes to the cell bodies and dendrites of neurons in several structures including the cerebral cortex, the hippocampus, the amygdala and the striatum. RIN1 does not seem to have a developmental role in the mouse brain as RIN1 expression is not seen in embryonic tissues and a null mutation does not disrupt the gross physiology of the brain (Dhaka et al., 2003). RIN1 expression begins after birth and steadily increases, reaching a stable maximum around postnatal day 21. This expression pattern, which parallels that of key postsynaptic signaling proteins such as CAMK2A (Cho et al., 1992), coincides with a period of rapid synaptogenesis in forebrain neurons (Aghajanian & Bloom, 1967), implying a role for RIN1 in synapse development, maturation and function.

The function of RIN1 appears to be dependent on cell type and the coexpression of collaborating proteins. In hematopoetic cells, for instance, RIN1 can enhance ABL-driven tumorigenesis (Afar et al., 1997) while there is evidence that RIN1 acts as a tumor suppressor in breast epithelial cells (MM & JC, unpublished data). This theme of context-dependent signaling has held true for neuronal RIN1 as well. Although RIN1 is expressed in multiple areas of the forebrain, the effects of RIN1 gene disruption appear most pronounced in the amygdala (Dhaka et al., 2003). This review will summarize our current understanding of the role of RIN1 in the brain and will explore potential molecular mechanisms for RIN1 function in plasticity.

RIN1 in Synaptic Plasticity and Aversive Memory Formation

Most of what we know of RIN1 function in the brain has come from studies of a Rin1 null mouse strain. Rin1^-/- mice appear physically normal but display alterations in amygdala function revealed by electrophysiological and behavioral assays (Dhaka et al., 2003). Compared to wild-type animals, Rin1^-/- animals showed elevated LTP in the amygdala (basolateral field postsynaptic potential) after excitation with a theta-burst protocol applied to the lateral amygdaloid nucleus (Figure 2). This effect appeared to be amygdala-specific as there was no difference in hippocampal LTP using this or several additional induction protocols. These results suggested an elevation in amygdala response to stimulation and this was confirmed with behavioral assays. Rin1^-/- mice displayed enhanced performance in two amygdala-dependent learning tasks: cued fear conditioning and conditioned taste aversion (Dhaka et al., 2003). Both behavioral tasks required the mice to learn an association between an unconditioned stimulus (US) and a conditioned stimulus (CS). In the fear conditioning assay, the US was a mild foot-shock and the CS was a tone. After training, Rin1^-/- mice showed increased fear response to the tone (CS) compared to wild-type mice (Figure 2). In conditioned taste aversion, mice were trained to associate nausea induced by LiCl (US) with the taste of saccharin-flavored water (CS). Rin1^-/- mice again showed a greater fear response to the CS, this time by consuming less sweetened water in a subsequent preference assay. Both training protocols indicated stronger US-CS association in the knockout than in wild-type. Together with the electrophysiology results, these behavioral assays demonstrated that deletion of Rin1 elevates amygdala function in response to stimulation. Stated another way, these findings suggest that RIN1 acts as an inhibitor of plasticity and learning in the amygdala. Importantly, Rin1^-/- mice did not have elevated levels of generalized anxiety, as measured by the Open Field paradigm (Dhaka et al., 2003) and Elevated Plus Maze (JMB and JC, unpublished), ruling out the possibility that their enhanced response in fear conditioning or conditioned taste aversion was caused by an increase in anxiety.

Figure 2. Rin1^-/- mice display increased amygdala function. Rin1^-/- mice have elevated basolateral amygdala LTP after theta-burst stimulation in the lateral amygdala (left). These mice also display enhanced learning in a tone-cued fear assay (right). Abbreviations: PSP, postsynaptic potential; TBS, theta-burst stimulation; PCS, pre-conditioned stimulus; CS, conditioned stimulus. (Copyright 2003 by the Society for Neuroscience)

The fact that Rin1-/- mice perform better than wild-type in fear conditioning and conditioned taste aversion should be viewed as a defect in learning and memory in the absence of RIN1. In fear conditioning, as in most learning tasks, the appropriate response is achieved through a balance of excitatory and inhibitory processes. The importance of inhibitory learning can be seen in human anxiety disorders, such as posttraumatic stress disorder, in which a person has difficulty suppressing a fear response based on a past experience (Craske, 1999). Therefore, the increased performance of Rin1^-/- mice in fear conditioning does not indicate a "smarter" mouse, so much as a mouse that is creating overly strong fear-based associations due to a deficit in normal inhibitory processes. Indeed, recent studies of fear extinction in Rin1^-/- mice provide further support that RIN1 may normally promote inhibitory processes in the amygdala (JB and JC, unpublished data).

Although RIN1 is expressed in the hippocampus at levels similar to those seen in the amygdala, no alterations in hippocampal LTP or in the hippocampus-dependent Morris water maze were seen in Rin1^-/- mice (Dhaka et al., 2003). It is possible that a function for RIN1 in this and other brain structures will be revealed by further electrophysiological and behavioral testing. Based on our current understanding of RIN1 function in both neuronal and non-neuronal tissues, RIN1 signaling is likely to be most critical in response to a limited spectrum of acute stimulations. Hence, it may be necessary to optimize the type, intensity and duration of stimulation for each region in order to uncover deficits conferred by a Rin1 null mutation. For example, the response increase of C57/129 Rin1^-/- mice in fear conditioning was optimal when using shock intensities below the conditioning threshold for wild-type mice. Rin1^-/- mice may show phenotypes in other brain areas if more specific and appropriately tailored behavioral assays are employed. Another possible explanation for the specificity of the Rin1^-/- phenotype may be the relative contributions from different types of neurons (e.g. excitatory vs. inhibitory) in different brain structures. If RIN1 has a disproportionate effect in excitatory versus inhibitory neurons, its absence would be expected to differentially impact the amygdala, which has a relatively larger proportion of inhibitory neurons than the hippocampus. Finally, RIN1 may have different functions depending on the prevalence and importance of its interaction partners in a given tissue. RIN1 directly signals through ABL and RAB5 but very likely operates through additional proteins as well. Understanding the role of each of these proteins in learning and memory will provide insight into potential mechanisms for RIN1 function in synaptic plasticity.

RAS Signal Transduction in Neuronal Plasticity

RAS (HRAS, KRAS, and NRAS) are GTPases that can be activated through diverse pathways. Upon activation, RAS proteins signal through multiple effector proteins, such as RAF, PI3K or RIN1. Because all effectors bind to the same region of activated RAS, the different effector pathways are inherently competitive. RIN1's binding affinity for RAS is only slightly weaker than that of RAF (Wang et al., 2002; Wohlgemuth et al., 2005), and RIN1 has been shown to compete with RAF in vitro and in vivo (Han & Colicelli, 1995; Wang et al., 2002). Given the ability of RIN1 to inhibit other RAS pathways, RIN1 may function in part by down-regulating RAS signaling through other effectors. Neuronal RAS signaling can be initiated by glutamate receptors, membrane depolarization or neurotrophin receptors. The resulting downstream effects include modification and/or redistribution of receptors and stimulation of new transcription (Kelleher et al., 2004; Kennedy et al., 2005; Thornton et al., 2003; Zhu et al., 2002). Yet, due to the complexity of RAS signaling, it has been difficult to untangle the relative contributions of each RAS effector. Indeed, it is not yet clear to what extent the downstream effects of RAS activation in neurons are mediated directly by RIN1, or if RIN1 instead functions mainly as a modulator of RAS signaling through other effectors

If RIN1 normally inhibits plasticity by directly transmitting RAS activation signals to RIN1 effectors (i.e. ABL and RAB5), the phenotype of the Rin1^-/- mouse may be viewed as a disruption of RAS signaling. However, if RIN1 functions in neurons primarily as an inhibitor of other RAS effector pathways, we might expect Rin1^-/- mice to model activation of RAS signaling. To date, all examples of abnormal inhibition or activation of RAS have shown disruption of synaptic function and reduced plasticity (Table 1). Mutations in SYNGAP1 and NF1, two neuronal inhibitors of RAS, have been studied in terms of neuronal plasticity. Syngap^+/- mice show deficits in hippocampal LTP (Kim et al., 2003; Komiyama et al., 2002) while Nf1^+/- mice show deficits in spatial memory as well as hippocampal LTP (Costa et al., 2002; Silva et al., 1997). Likewise, disruption of RAS activators also leads to deficits in plasticity. Mice lacking GRF1, a RAS activator expressed at high levels in the forebrain, show deficits in LTP and learning in both the amygdala (Brambilla et al., 1997) and the hippocampus (Giese et al., 2001). As illustrated by the variety of neuronal defects seen in these mice, any alteration in regulating the magnitude of RAS signaling can be detrimental to synaptic plasticity. It remains to be determined precisely how RAS signaling is altered in Rin1^-/- mice, but the observed enhancement of amygdala LTP and learning suggest that more than changes in the intensity of RAS signaling are involved.

Table 1. Plasticity Effects of Disruption in RAS Signal Transduction Using Mouse Model Systems.

RAS Effectors

If RIN1 functions by altering RAS signaling in neurons, it might do so by inhibiting other RAS effectors such as the RAF/MEK/ERK cascade and PI3K. Both ERK and PI3K have been implicated as positive factors in synaptic plasticity. Inhibitors of ERK interfere with LTP in the hippocampus (English & Sweatt, 1997), the amygdala (Huang et al., 2000) and some regions of the cortex (Berman et al., 1998; Hebert & Dash, 2002). ERK signaling, which has emerged as a major pathway in postsynaptic plasticity, is thought to mediate short-term changes such as insertion of AMPA receptors and synaptic structural changes as well as long-term effects such as alterations in gene expression (Kelleher et al., 2004; Martin et al., 1997; Thomas & Huganir, 2004; Wu et al., 2001). There are also some forms of plasticity that rely on PI3K (Kelly & Lynch, 2000; Lin et al., 2001; Sanna et al., 2002). Opazo et al. showed that hippocampal LTP induced by presynaptic stimulation paired with post-synaptic depolarization is sensitive to inhibitors of PI3K but not of ERK (Opazo et al., 2003). There is also substantial evidence that ERK and PI3K pathways interact, as PI3K inhibitors block ERK activation mediated by the NMDA receptor and synaptic stimulation (Opazo et al., 2003). The ultimate effects of PI3K activation are still unclear, but it is thought that, like ERK, PI3K is important for insertion of AMPA receptors at the postsynaptic membrane (Man et al., 2003). The intricacy of neuronal RAS signaling has made it difficult to fully delineate the role of each RAS regulator and effector. As pathways downstream of RAS can influence each other (Kennedy et al., 2005), it may be that the final effect of RAS signaling on the synapse is determined by the summation of signals from different effectors. Therefore, inhibition of one or more of these pathways by RIN1 could alter the polarity or magnitude of synaptic plasticity.

ABL Signaling Downstream of RIN1

The ABL family tyrosine kinases (ABL1 and ABL2) bind F-actin and influence cytoskeletal remodeling via phosphorylation of several regulatory proteins (Wang et al., 2001; Woodring et al., 2003; Woodring et al., 2002). ABL kinases localize to both pre- and postsynaptic sites in hippocampal neurons (Moresco & Koleske, 2003). RIN1 has been shown to increase ABL kinase activity and ABL-mediated regulation of cytoskeletal remodeling (Hu et al., 2005), suggesting that RIN1 may function in neurons to modulate cytoskeletal remodeling at synapses. Recent research has indicated that plasticity and learning are often accompanied by synaptic structural changes, such as dendritic spine enlargement, which may accommodate insertion or depletion of proteins at the synapse (Carlisle & Kennedy, 2005; Okamoto et al., 2004). While most studies of neuronal ABL have focused on developmental effects (Koleske et al., 1998; Moresco and Koleske, 2003), there is evidence that a change in ABL activity might affect mature neurons. One relevant observation is that ABL associates with EphB2 (Yu et al., 2001), a protein implicated in NMDA receptor clustering and synapse development (Dalva et al., 2000; Henderson et al., 2001). Although ABL and EphB2 have not been shown to interact in neuronal tissues, the potential for EphB proteins to signal through ABL proteins suggests that these tyrosine kinases may participate in activity-induced synapse formation. Additionally, Moresco et al. found that Abl1^-/- and Abl2^-/- mice show deficits in short-term synaptic strength increases (prepulse facilitation) in the hippocampus (Moresco et al., 2003). Taken together, these data suggest a role for ABL, and by implication its activator RIN1, in synaptic plasticity.

RAB5 Signaling Downstream of RIN1

RIN1 has a VPS9 domain with GEF activity for RAB5 (Tall et al., 2001), a GTPase that regulates clathrin-mediated endocytosis from the cell surface to early endosomes (de Hoop et al., 1994; Zerial and McBride, 2001). Recently, RAB5 was found to play a crucial role in both metabotropic glutamate receptor-dependent (Huang et al., 2004) and NMDA receptor-dependent LTD in the hippocampus (Brown et al., 2005). Overexpression of RAB5 was sufficient to cause a decrease in the number of AMPA receptors on the postsynaptic surface, while a dominant negative form of RAB5 prevented endocytosis of synaptic AMPA receptors (Brown et al., 2005). Because many forms of LTD are thought to rely on decreased levels of synaptic AMPA receptor (Malenka & Bear, 2004), these data reveal RAB5 as an important mediator of LTD. As an activator of RAB5-mediated glutamate receptor endocytosis, RIN1 might function as an activator of LTD and/or an inhibitor of LTP.

Conclusions

Behavioral and electrophysiological evidence directly implicate RIN1 as a negative regulator of the synaptic plasticity that underlies learning and memory in the amygdala. An open question regarding RIN1 is why the effects so far observed in Rin1^-/- mice are amygdala specific. RIN1 expression in other regions such as the hippocampus, striatum and frontal cortex suggests that RIN1 has a normal function in these regions. Amygdala hyperactivation may simply be the most pronounced phenotype of Rin1^-/- mice due to the neuronal populations or protein expression profiles that are unique to that region. However, additional roles for RIN1 are likely to be uncovered by further experiments based on additional knowledge of RIN1 signaling.

The current challenge in this field is to uncover the molecular mechanisms explaining RIN1 function at the synapse. Some scientists have reasoned that the brain's immense capacity for complex responses is due to the complexity of interactions between neuronal signaling pathways. RIN1 is placed within several of those pathways and its binding partners provide potential models for regulation of plasticity. RIN1 may function to decrease synaptic strength by inhibiting RAS signaling through other effectors, by enhancing the effects of ABL on the postsynaptic cytoskeleton or by activation of RAB5-mediated endocytosis of neurotransmitter receptors (Figure 3). Importantly, these models are not mutually exclusive and it seems likely that RIN1 acts through more than one pathway. For example, RIN1 should be capable of decreasing synaptic levels of AMPA receptor through two pathways: by inhibiting RAS-mediated delivery of AMPA receptors and by increasing endocytosis of AMPA receptors via RAB5. Future research should clarify the role of RIN1 in synaptic plasticity as well as expand our understanding of the mechanisms underlying learning and memory.

Figure 3: Model for RIN1 function in Neuronal Plasticity. Current knowledge of RIN1 signaling pathways suggest three potential effects on neuronal plasticity (see text for explanation).

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