Neuronal plasticity is crucial to mammalian brain development, function, and the generation of behaviors, including learning and memory. Deficits in neuroplasticity and in the balance of excitation and inhibition have been hypothesized to underlie a number of neurodevelopmental conditions, including autism spectrum (AS). AS encompasses heterogenous conditions and disorders characterized by core behavioral changes. Despite the association of hundreds of genes with AS, how each one contributes to behavioral changes at the molecular and neuronal levels remains relatively unknown. In C. elegans, the GABAergic neuron DVB undergoes experience-dependent structural plasticity characterized by branching and neurite outgrowth in adult males, impacting excitatory and inhibitory balance and behavioral output. We are using this simple model of neuroplasticity to screen 50 conserved autism-associated genes for roles in GABAergic neuronal plasticity and maintenance of excitatory and inhibitory balance. Among the genes we have tested, males mutant for
rbr-2/KDM5B,
snf-11/SLC6A1,
set-4/KMT5B, or
unc-10/RIMS1 did not show significant changes in DVB morphology, while mutations in
chd-1/CHD1,
daf-18/PTEN,
gap-2/SYNGAP1, and
unc-44 resulted in increased DVB neurite outgrowth in adult males.
unc-44 is the worm ortholog of ankyrin (ANK2), a high confidence autism-associated gene that is important for cytoskeleton organization. In
unc-44 loss of function mutant males, we found branching and neurite outgrowth to be nearly doubled at days 1 and 3 of adulthood. We are currently testing
fkh-7/FOXP1,
slt-1/SLIT1,
lin-59/ASH1L,
nmr-2/GRIN2B,
kqt-1/KCNQ3, and
cca-1/CACNA1H. We will analyze the role of these genes on DVB-dependent behavioral plasticity and determine molecular mechanisms and potential interactions for genes with identified phenotypes.