Ras and Rap signaling in synaptic plasticity and mental disorders

Abstract

The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyperactivation of Ras/ Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a "happy-medium" dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with several mental disorders associated with learning disability (e.g., Alzheimer's disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases.

Fig. 1. Model for synaptic AMPA-R trafficking

LS: lysosome; Slot: hypothesized protein(s) that are delivered and removed with AMPA-Rs during activity-dependent synaptic potentiation and depression, respectively; V/ES: vesicles/endosomes.

Fig. 2. Time course of AMPA-R trafficking during LTP, LTD and depotentiation

A. Steady state synaptic AMPA-R-mediated response amplitudes in CA1 pyramidal neurons expressing Ras(ca)-GFP or Ras(dn)-GFP and neighboring non-expressing control neurons before and after LTP-inducing pairing. B. Steady state synaptic AMPA-R-mediated response amplitudes in CA1 pyramidal neurons expressing Rap1(ca)-GFP or Rap1(dn)-GFP and neighboring non-expressing control neurons before and after LTD-inducing pairing. C. Steady state synaptic AMPA-R-mediated response amplitudes in CA1 pyramidal neurons expressing Rap1(ca)-GFP or Rap1(dn)-GFP and neighboring non-expressing control neurons before and after LTP-and depotentiation-inducing pairings. D. Subtracting synaptic AMPA-R-mediated responses in expressing neurons from neighboring non-expressing control neurons gives the time course of LTP-, LTD- and depotentiation-induced alterations of synaptic efficacy. Note that the data points are fitted with a single exponential function to estimate rate time constants of AMPA-R trafficking during LTP, LTD and depotentiation. The reanalysis uses the data collected in the previous studies (Zhu and others 2002; Zhu and others 2005).

Fig. 3. Model for Ras signaling-regulated synaptic delivery of AMPA-Rs during LTP

BRaf: V-raf murine sarcoma viral oncogene homolog B; CaMKII: calcium/calmodulin-dependent protein kinase II; ERK: extracellular signal-regulated kinase kinase; LS: lysosome; MEK: extracellular signal-regulated kinase; PI3K: phosphoinositide 3-kinase; PKB: protein kinase B; RasGEF: Ras activators; RasGAP: Ras inactivators; Slot: hypothesized protein(s) that are delivered or removed with AMPA-Rs; V/ES: vesicles/endosomes.

Fig. 4. Model for Rap1 signaling-regulated synaptic removal of AMPA-Rs during LTD

LS: lysosome; P38: p38 mitogen-activated protein kinases; Rap1GEF: Rap1 activators; Rap1GAP: Rap1 inactivators; Slot: hypothesized protein(s) that are delivered or removed with AMPA-Rs; V/ES: vesicles/endosomes.

Fig. 5. Model for Rap2 signaling-regulated synaptic removal of AMPA-Rs during depotentiation

JNK: c-Jun amino-terminal kinase; LS: lysosome; PP2B: protein phosphatase 2B; Rap2GEF: Rap2 activators; Rap2GAP: Rap2 inactivators; Slot: hypothesized protein(s) that are delivered or removed with AMPA-Rs; TNIK: Traf2- and NCK-interacting kinase; V/ES: vesicles/endosomes.

Fig. 6. Ras signaling molecules with mutations linked to mental disorders

BRaf: V-raf murine sarcoma viral oncogene homolog B; CaMKII: calcium/calmodulin-dependent protein kinase II; ERK: extracellular signal-regulated kinase kinase; JNK: c-Jun amino-terminal kinase; LS: lysosome; MEK: extracellular signal-regulated kinase; NF1: neurofibromin 1, a RasGap; PI3K: phosphoinositide 3-kinase; PKB: protein kinase B; PP2B: protein phosphatase 2B; SHP-2: SH2 domain-containing protein-tyrosine phosphatase PTPN11; RSK: ribosomal S 6 serine/threonine kinase; SOS: son of sevenless, a RasGEF; TSC: tuberous sclerosis complex.