Proteomic Characterization of Striatal Neurabin Interactome and Its Sex Specific Impact on Motor Behavior

The striatum serves
as the primary input nucleus of the basal ganglia.
Reversible protein phosphorylation in the post synaptic density (PSD)
of medium spiny neurons (MSNs) modulates inputs from striatal afferents.
The context dependent regulation of PSD protein phosphorylation in
direct-pathway medium spiny neurons (dMSNs) and indirect-pathway medium
spiny neurons (iMSNs) works to differentially and synergistically
impact striatal physiology and the execution of motor programs. An
important regulator of PSD protein phosphorylation is protein phosphatase
1 (PP1), which obtains substrate specificity through the action of
PP1 targeting proteins. While prior work has demonstrated the global
and cell type-specific impact of the PP1 targeting protein, spinophilin,
on striatal motor behaviors like the accelerating rotarod task and
amphetamine sensitization, the role of its homologue, neurabin, is
yet to be elucidated. Using proteomics approaches, we determined that
striatal neurabin associates with pre and postsynaptic proteins that
mediate glutamatergic synapse function. Moreover, we found that global
loss of neurabin enhanced rotarod motor learning but had no impact
on amphetamine sensitization. Interestingly, using novel conditional
neurabin knockout mouse lines, we found that loss of neurabin in dMSNs,
but not iMSNs, enhanced performance on the accelerating rotarod task
and that these effects were specific for male mice. These data highlight
neurabin’s particular importance to the striatal glutamatergic
synapse and uncover a sex and cell type specific role for this synaptic
protein in uniquely limiting skill motor learning but not psychomotor
sensitization.