The ability to acquire new memories and learn from environmental queues requires changes in neuronal gene expression. This reflects both nuclear events (e.g. changes in transcription) as well as local events within stimulated dendritic spines that have received trans-synaptic signals. A local event of critical importance is alterations in the translation of dendritic spine mRNAs that presumably transduce the electrical/chemical synaptic signal into biochemical (protein) signals. Multiple neurodevelopmental diseases including Fragile X Syndrome and neurodegenerative diseases such as Alzheimer’s have inherited or acquired defects in these processes, possibly explaining the reduced cognitive function in these disorders.
We hypothesized that Pin1 played a role in dendritic translation due to its interaction with key signaling kinases including Erk, PI-3-K and Akt that are triggered by neurotransmitters. Consistent with this, Pin1 blockade or KO increased the rate of basal translation in synaptoneurosomes (SN), brain preparations that are highly enriched for resealed pre- and post-synaptic vesicles and thus contain all of the signaling machinery present in vivo. Wild type SN increased translation after stimulation with glutamate to the level seen in KO preparations suggesting Pin1 was required for the regulation of protein synthesis.
As translation is required for long term potentiation (LTP), an electrophysiologic correlate of memory acquisition, we compared potentiation after theta burst stimuli in brain slices from WT vs. KO mice. Consistent with the above results, KO slices showed significantly greater LTP than WT that was blocked in both WT as well as KO preparations by the protein synthesis inhibitor, anisomycin.
Based on these data as well as prior published work, we asked if Pin1 interacted with PKMζ, a constitutively active PKC isoform highly expressed in neurons whose activity is required for memory retrieval and LTP. Immuno-precipitation revealed that Pin1 and PKMζ interacted and additional studies showed that PKMζ phosphorylated Pin1, rendering it inactive. Blockade of PKMζ also inhibited dendritic protein synthesis irrespective of the presence of Pin1, suggesting it functioned downstream of and possibly mediated the effects of Pin1 on translation.
We are planning on establishing the behavioral and intellectual consequences of Pin1 KO in adult animals, as well as pursuing the mechanisms by which Pin1 affects protein synthesis utilizing a combination of in vitro systems (neuronal cultures and SN) s well as conditional KO mice lacking Pin1 in different regions of the brain.