Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

Cahill, Michael E.; Xie, Zhong; Day, Michelle; Photowala, Huzefa; Barbolina, Maria V.; Miller, Courtney A.; Weiss, Craig; Radulovic, Jelena; Sweatt, J. David; Disterhoft, John F.; Surmeier, D. James; Penzes, Peter

doi:10.1073/pnas.0904636106

Cited by 153 publications

(210 citation statements)

References 50 publications

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“…The deficit in NMDA receptor levels did not prevent synapse formation in the developing brain of NR1-KD mice, but was sufficient to reduce spine density after adolescence, suggesting a greater necessity for intact NMDA receptor levels during synapse elimination or maintenance. Several recent studies illustrate how the cellular and behavioral consequences of developmental perturbations in neuron function may not become evident until adulthood (40)(41)(42)(43). Collectively, these studies and the present one demonstrate how genetic factors may act in an age-dependent fashion to produce adult-onset symptoms of CNS conditions associated with aberrant synaptic function.…”

Section: Discussionmentioning

confidence: 77%

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Ramsey

Milenkovic

Oliveira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an agedependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapsespecific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia-1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.glutamate | neurodevelopmental A defining feature of neurons is their ability to alter the number and strength of synaptic connections with experience. At the cellular level, changes in synapse number, or postsynaptic spine density, occur with learning and memory formation (1) or exposure to psychoactive drugs (2), and in neurodevelopmental diseases including schizophrenia (3, 4), fragile-X mental retardation (5), and Rett syndrome (6). At the molecular level, NMDA-type glutamate receptors have long been appreciated for their role in the formation and maintenance of glutamatergic synapses (7), and as mediators of synaptic plasticity (8). Several studies have shown a positive correlation between NMDA receptor activity and spine density (9-12), with notable exceptions (13,14). However, the molecular mechanisms by which NMDA receptors regulate spine density remain to be fully elucidated. In the case of disease states such as schizophrenia, a fuller understanding of this molecular machinery may point to new therapeutic strategies.The striatum represents an ideal brain region in which to further explore the biochemical mechanisms by which NMDA receptors regulate spine density, because the vast majority of neurons (95%) within this brain structure are medium spiny neurons (MSNs), which have densely spinous dendrites, upon which glutamate and dopamine afferents converge (15,16). This neuronal homogeneity allows for ex vivo biochemical preparation of synaptic proteins from a nearly homogenous neuronal substrate. MSNs are thought to be a principal site of action of antipsychotic drugs because they express the highest levels of D2 dopamine receptors (17). Furthermore, they participate in many of the cognitive and limbic behaviors that are altered in schizophrenia (17, 18).We hypothesized that reduced NMDA receptor funct...

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Section: Discussionmentioning

confidence: 77%

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Ramsey

Milenkovic

Oliveira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies in Kalirin KO mice have found moderately reduced spine density in cortical neurons (19), but either no change (10,19) similarity, it is reasonable to infer that Kalirin and Trio serve similar roles in supporting synaptic structure. Interestingly, we found that knockdown of Kalirin or Trio expression individually resulted in a largely AMPAR-specific dysfunction, with NMDAR function mostly preserved, indicating that the total number of synapses in hippocampal CA1 pyramidal neurons is preserved by eliminating Kalirin or Trio alone.…”

Section: Discussionmentioning

confidence: 98%

Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

Herring

Nicoll

2016

Proc. Natl. Acad. Sci. U.S.A.

112

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The molecular mechanism underlying long-term potentiation (LTP) is critical for understanding learning and memory. CaMKII, a key kinase involved in LTP, is both necessary and sufficient for LTP induction. However, how CaMKII gives rise to LTP is currently unknown. Recent studies suggest that Rho GTPases are necessary for LTP. Rho GTPases are activated by Rho guanine exchange factors (RhoGEFs), but the RhoGEF(s) required for LTP also remain unknown. Here, using a combination of molecular, electrophysiological, and imaging techniques, we show that the RhoGEF Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Furthermore, we show that CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression, and that preventing CaMKII signaling through Kalirin and Trio prevents LTP induction. Thus, our data identify Kalirin and Trio as the elusive targets of CaMKII phosphorylation responsible for AMPA receptor up-regulation during LTP.

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“…Accordingly, Kidins220 is enriched at the postsynaptic density (Wu and Chao, personal communication), and dendriticspine stability is significantly reduced in Kidins220 -/+ mice (Wu et al, 2009). It is interesting in this context that Kalirin has a major role in dendritic-spine morphogenesis (Cahill et al, 2009;Ma et al, 2003;Ma et al, 2008;Penzes et al, 2003;Penzes and Jones, 2008), suggesting a new connection by Kidins220 between these pathways.…”

Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

Neubrand

Thomas

Schmidt

et al. 2010

Journal of Cell Science

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SummaryNeurite extension depends on extracellular signals that lead to changes in gene expression and rearrangement of the actin cytoskeleton. A factor that might orchestrate these signalling pathways with cytoskeletal elements is the integral membrane protein Kidins220/ARMS, a downstream target of neurotrophins. Here, we identified Trio, a RhoGEF for Rac1, RhoG and RhoA, which is involved in neurite outgrowth and axon guidance, as a binding partner of Kidins220. This interaction is direct and occurs between the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 colocalise at the tips of neurites in NGF-differentiated PC12 cells, where F-actin and Rac1 also accumulate. Expression of the ankyrin repeats of Kidins220 in PC12 cells inhibits NGF-dependent and Trioinduced neurite outgrowth. Similar results are seen in primary hippocampal neurons. Our data indicate that Kidins220 might localise Trio to specific membrane sites and regulate its activity, leading to Rac1 activation and neurite outgrowth.

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Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

Cited by 153 publications

References 50 publications

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

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