Mechanisms Stabilizing Synaptic Plasticity Are Impaired In Models of Autism Associated Disorders

Consolidation (stabilization) of long-term potentiation (LTP), and quite possibly memory, requires the rapid reorganization of the sub-synaptic cytoskeleton. This process involves two signaling cascades, one that initiates actin polymerization and a second that stabilizes the newly formed actin filaments. We have begun testing if defects in these processes contribute to synaptic disturbances in rodent models of cognitive, and autism-related, disorders, including the Fmr1-knockout (Fmr1-KO) mouse model of Fragile X Syndrome. Hippocampal slices prepared from Fmr1-KO mice proved to have two synaptic plasticity deficits: 1) a modest elevation in the activity-threshold for inducing LTP expression and 2) a slower than normal rate of LTP consolidation. Actin polymerization within spines in the minutes following LTP induction was not measurably different in Fmr1-KO slices vs wild-type controls (Lauterborn et al, 2007), suggesting that the LTP-consolidation defect involves the actin filament stabilization pathway. In accord with this, we have found that the stabilization of LTP involves the small GTPase Rac and its effector p21-activated kinase (PAK), and partial suppression of PAK is reported to reduce synaptic abnormalities in the Fmr1-KO mouse (Hayashi et al, 2007). We are currently attempting to isolate the defective step(s) in signaling through the Rac>PAK filamentous actin stabilization pathway in the Fmr1-KOs. In parallel, we are evaluating the LTP consolidation problems in the BTBR T+ tf/j inbred strain (MacPherson et al. 2008 and unpublished data) that exhibits behavioral traits associated with autism (Macfarlane et al., 2007) with an interest in the possibility of shared impairments in activity-regulation of the spine actin cytoskeleton in the Fmr1-KO and BTBR strains. In all, it is possible that critical synaptic defects in models of autism-related disorders arise from relatively small disturbances to the specialized cellular machinery normally used to convert recently learned material into long-term memory.