Multiple behaviors disrupted in autism spectrum disorders (ASDs), including the integration of sensory stimuli and social interaction, are associated with the dysfunction of striatal synapses. Striatal dysregulation is reported in imaging studies of ASD and many genetic alleles associated with ASD are clustered within striatal regulatory pathways. Little is known, however, about postnatal maturation of striatal neurons and alterations to this process in ASDs.
Medium spiny neurons (MSNs), the principal neurons of the striatum, are highly excitable in early life and readily driven to fire by excitatory cortical and thalamic inputs. Adult MSNs are far less excitable and require multiple coordinated synaptic inputs to fire, a feature required for normal mature sensorimotor learning. David Sulzer’s laboratory has found that this change in MSNs excitability is a normal step in maturation resulting from the increased conductance by inwardly rectifying potassium channels, Kir2.1 and Kir2.3. This results in mature MSNs that require substantial excitatory input to fire, but once that state is reached, the current turns off, and the neuron can fire repeatedly. In this way, the increase in Kir currents during adolescence allows adult MSNs to act as a high-pass filter that precisely determines which corticostriatal circuits select an action. Separately, studies have shown that hyperactivation of mTOR, is implicated in multiple forms of ASDs, including monogenic disorders such as tuberous sclerosis (TS). In individuals with ASD and in mouse TS models, the normal pruning of cortical synapses is absent due to overactivation of mTOR and decreased macroautophagy. Reinstating normal mTOR levels and macroautophagy with rapamycin normalizes ASD-model behaviors in mice1.
The Sulzer group has now gathered preliminary data that integrate these two findings, demonstrating a maturation- and mTOR-dependent decrease in intrinsic excitability in MSNs that relies on macroautophagy-dependent regulation of Kir currents. When normal MSN macroautophagy is blocked, the MSNs do not develop increased Kir currents and remain in the juvenile, hyperexcitable state throughout life. Based on these data, Sulzer hypothesizes that the normal age-dependent reduction in intrinsic MSN excitability during adolescence is critical for normal striatal function and, when disrupted, leads to ASD-like behaviors.
To assess this hypothesis, Sulzer’s team will examine if the normal developmental decrease of MSN excitability is disrupted in TS complex and Fmr1 ASD models and determine if MSN hyperexcitability is associated with ASD-like pathophysiology. The group will elucidate cell-intrinsic mechanisms that regulate this transition. Sulzer’s team will also address the therapeutic relevance of targeting MSN macroautophagy and its effects on MSN intrinsic excitability for ASD treatment.