Abnormal kalirin signaling in neuropsychiatric disorders

Abstract

Changes in dendritic spines structure and function play a critical role in a number of physiological processes, including synaptic transmission and plasticity, and are intimately linked to cognitive function. Alterations in dendritic spine morphogenesis occur in a number of neuropsychiatric disorders and likely underlie the cognitive and behavioral changes associated with these disorders. The neuronal guanine nucleotide exchange factor (GEF) kalirin is emerging as a key regulator of structural and functional plasticity at dendritic spines. Moreover, a series of recent studies have genetically and functionally linked kalirin signaling to several disorders, including schizophrenia and Alzheimer's disease. Kalirin signaling may thus represent a disease mechanism and provide a novel therapeutic target.

Keywords: Alzheimer's disease; Genetic; Glutamatergic; Mental disorder; Postmortem; Schizophrenia.

Figure 1. Kalirin-7 is localized to dendritic spines and modulates dendritic spine morphogenesis

(A) This schematic of kalirin isoforms and domains shows the N-terminal Sec14p domain, followed by nine spectrin-like repeats common to all kalirin isoforms. The Dbl homology (DH) and pleckstrin homology (PH) domains confer kalirin’s GEF activity. The first GEF domain activates Rac1 and is present in kalirin-7, -9 and -12. Kalirin-7 also has a unique C-terminal PDZ-binding domain. Kalirin-9 and -12 have an SH3 domain and a second GEF domain that activates RhoA. Kalirin-12 has C-terminal fibronectin III-like and immunoglobulin-like domains as well as a kinase domain. (B) Kalirin-7 is localized to dendritic spines of cortical pyramidal neurons.

Figure 2. Kalirin-7 interacts with schizophrenia-associated proteins

Under non-pathological conditions, kalirin interacts with a number of schizophrenia-associated proteins. Activation of postsynaptic NMDARs leads to increased trafficking of AMPARs to the post-synaptic density. NMDAR activation also leads to dissociation of the PDS-95/DISC1/kalirin-7 complex, allowing kalirin-7 to activate Rac1. Post-synaptic erbB4 receptors are activated by NRG1 and modulate dendritic spines in a kalirin-dependent manner. 5-HT_2A receptor activation also regulates spine density through kalirin. Kalirin-7 activates Rac1 by exchanging GDP for GTP. Rac1 in turn activates PAK, which then initiates actin remodeling. Kalirin-7, DISC1, erbB4, NRG1, 5-HT_2A, PAK2 and PAK3 have been genetically associated with schizophrenia.

Figure 3. Kalirin-7 interacts with Alzheimer’s disease-associated proteins

Amyloid β oligomers bind to dendritic spines in AD, leading to decreased surface expression of NMDARs and EphB2 receptors. This likely causes decreased kalirin/Rac/PAK signaling, leading to synapse loss and cognitive impairment. Aβ oligomers, kalirin-7, and PAK have been associated with AD.

Figure 4. Reductions in kalirin isoforms relative to control in Braak stages 3–5

(A) and Braak stage 6 (B) subjects. (C) Aβ ratio by Braak stage. AD−P: AD without psychosis; AD+P: AD with psychosis; * p < 0.05, ** p<0.001.