RIM1α and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia

Abstract

Several presynaptic proteins involved in neurotransmitter release in the CNS have been implicated in schizophrenia in human clinical genetic studies, in postmortem studies, and in studies of putative animal models of schizophrenia. The presynaptic protein RIM1␣ mediates presynaptic plasticity and cognitive function. We now demonstrate that mice deficient in RIM1␣ exhibit abnormalities in multiple schizophrenia-relevant behavioral tasks including prepulse inhibition, response to psychotomimetic drugs, and social interaction. These schizophrenia-relevant behavioral findings are relatively selective to RIM1␣-deficient mice, as mice bearing mutations in the RIM1␣ binding partners Rab3A or synaptotagmin 1 only show decreased prepulse inhibition. In addition to RIM1␣'s involvement in multiple behavioral abnormalities, these data suggest that alterations in presynaptic forms of short-term plasticity are linked to alterations in prepulse inhibition, a measure of sensorimotor gating.

Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex

“…Consistent with this concept, mounting evidence from gene profiling, genetic association, and proteomic analyses indicates that alterations in presynaptic function contribute to the etiology of schizophrenia (Chen et al, 2004;Lee et al, 2005;Behan et al, 2009;Maycox et al, 2009;Faludi and Mirnics, 2011). In addition, several studies have reported alterations in presynaptic function or short-term synaptic plasticity in other mouse models of schizophrenia (Jentsch et al, 2009;Talbot, 2009;Blundell et al, 2010;Earls et al, 2010;Kvajo et al, 2011). Critically, our study extends on these findings by revealing an integrated disease mechanism that links presynaptic dysfunction with corresponding effects on higher-order circuit, network, and cognitive functions.…”

Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission

“…The Morris water maze task was conducted essentially as described previously (Powell et al, 2004;Tabuchi et al, 2007). Briefly, a white, circular pool 1.2 m in diameter was filled with water (22 Ϯ 1 C) made opaque with nontoxic, "gothic white" liquid tempera paint, and a circular platform (10 cm in diameter) was submerged ϳ1 cm beneath the surface of the water.…”

“…Coordination and motor learning were tested using a rotarod essentially as described previously (Powell et al, 2004). Mice were placed on a stationary rotarod (IITC Life Sciences) in a well lit room that was then activated and accelerated from 0 to 45 revolutions/ min over 5 min.…”

“…This test was performed as described previously (Powell et al, 2004;Blundell et al, 2010b). Mice were placed on a black, anodized plate that was held at a constant temperature of 52°C (IITC Life Sciences model 39 hotplate) covered with a Plexiglas enclosure.…”

“…Dark/light. The dark/light test was performed as described previously (Powell et al, 2004). Briefly, the dark/light apparatus consisted of two chambers (each chamber was 25 ϫ 26 cm), one brightly lit (ϳ2900 lux) and the other kept dark with a small door (7 ϫ 7 cm) separating the two.…”