The Role of SRC Tyrosine Kinase in Synaptic Plasticity and Neurologica Disorder

The non-receptor protein tyrosine kinase Src is expressed throughout the central nervous system and is involved in diverse biological functions like cell growth, differentiation, and postsynaptic signalling. Despite the well-documented functions of Src in hippocampal synaptic plasticity, roles in social behaviours, motor function, cognition, and synaptic signalling in other brain regions remain largely untested. This work investigates the neurocellular and behavioural effects of in-vivo inhibition and disinhibition of the Src tyrosine kinase pathway in mice. To this end, we employed a cell permeant Src inhibitory peptide, mutant mice harbouring a loss-of-function point mutation in Src, and a mutant mouse with deficits in the inhibitory C-terminal Src kinase (Csk). Alterations in Src signalling were associated with profound changes in NMDA receptor signalling, synaptic plasticity, motor function, cued fear conditioning, and a variety of social behaviours, underscoring the ubiquity and importance of Src signalling in the mammalian central nervous system. Blocking the interaction of the Src tyrosine kinase with the NMDAR complex impaired auditory conditioned fear memory and social recognition. Inhibition of Src-NMDAR interactions also attenuated NR2B phosphorylation and decreased NR2B surface expression in the amygdala. Furthermore, at the lateral to basolateral nucleus pathway (LA-BLA), inhibition of Src impaired long-term potentiation. Mice harbouring a Src point mutation (Src(thl/thl) mice) exhibited behavioural abnormalities and growth retardation. We also observed differences in behaviour phenotypes analogous to mouse models of Williams-Beuren syndrome (WBS) and humans with WBS . WBS is neurodevelopmental disorder characterized by distinctive facial features, hypersociability, mild to moderate mental retardation, and a unique cognitive disability (Meyer-Lindenberg et al., 2006). Sociability and social vocalization were increased in three different social affiliation tasks in Src(thl/thl) mice. Mutant mice exhibited hyperactivity in the open field and spent significantly less time in the centre of the open field. Also, motor function was impaired in three different motor performance tasks. The Src(thl/thl) mice showed an enhanced startle response to loud stimuli, impaired cued fear conditioning, and deficient visiospatial memory in the Morris water maze. Furthermore, Src(thl/thl) mice were not able to learn a visual object recognition task. These results underscore the importance of Src in an array of behavioural, motor, and cognitive functions in mice. The C-terminal Src kinase (Csk) acts to suppress Src activity, so Csk(+/-) mice were employed to examine the behavioural impact of enhanced Src signalling. Decreased Csk expression led to enhanced long-term and short-term social olfactory recognition and social transmission of food preference. We also found elevated NR2B phosphorylation in the olfactory bulb and amygdala, two brain regions critical for the behavioural expression of anxiety and social recognition in mice. Deficiencies in the Src tyrosine kinase pathway were associated with impaired synaptic plasticity in the amygdala and behaviour disturbances that are relevant to WBS. Conversely, up-regulation of the Src tyrosine kinase pathway by reducing Csk expression increased social olfactory cognition. A more detailed understanding of the Src pathway could facilitate the development of new treatments for diseases characterized by aberrant social behaviours.

Advisor: Roder, John C.