We try to understand the discrepancy in GABA concentration measurements in ASD and the competence, albeit of small abundance, of the comorbidity between autism and epilepsy under the broad assumption that these disorders originate from different E/I ratios. Recent evidence from human induced pluripotent stem cell (hiPSC) studies and from EEG measurements implicates excessive gamma-aminobutyric acid (GABA) signaling as a key etiological factor in autism spectrum disorders (ASD). On the other hand, epilepsy is known to be due to excess glutamate. These dual etiologies agree well with ~ 90% of people with ASD. So, how can there exist a comorbidity of these conditions in one person, even though found in only 10% of patients? We show that "Excess GABA" encompasses distinct neurobiological mechanisms, which may account for the variability in excitatory/inhibitory (E/I) ratio and GABA concentration measurements reported in ASD literature and explain the possibility of the comorbidity. This study proposes a classification of three GABA surplus dysregulation modes: Type A (excess GABAergic neurons/synapses), Type B (reduced glutamatergic neurons/synapses), Type C (elevated extracellular GABA) and one GABA deficient dysregulation mode, Type RC (reduced extracellular GABA), that can inform personalized therapeutic strategies for each type (e.g., Type C might be targeted by GABA transport inhibitors) and reconcile the ASD experimental inconsistencies. Moreover, Types A and/or B combined with Type RC could be the condition enabling the combined ASD-epilepsy disorder and Types A and/or B combined with Type C could be the condition enabling the combined ASD-absence disorder.
Rabinovitch et al. (Tue,) studied this question.