Disruptions in the neuron-astrocyte metabolic interactions are widely recognized as a key contributor to various neurological disorders. However, the systems level mechanisms underlying the roles of these disruptions in diseased states are poorly understood. Recent findings show that the brain-type fatty acid binding protein 7 (FABP7), a circadian-regulated protein that regulates subcellular trafficking of fatty acids, acts as an integrator of sleep and neuron-astrocyte metabolic coupling. FABP7 is implicated in neurological disorders such as epilepsy, traumatic brain injury (TBI), and neurodegenerative diseases (Alzheimer’s). Recent experimental studies further show that the seizure-induction threshold by electrical shock is increased in mice with FABP7 knocked out compared to wild-type (WT), but only during their waking period. Here, we evaluated the role of FABP7 in neuron-astrocyte metabolism and its mechanistic roles in seizure susceptibility using computational metabolic modeling approaches. We recurated the iMM1865 model to generate a high-quality genome-scale metabolic (GSM) model for a generic mouse cell (Mus musculus) by addressing the deficiencies in fatty acids metabolism, mass balancing, and metadata. The iMAT tool was used to reconstruct cell-line specific neurons and astrocytes GSM models. Both models were used with GECKO 3.0 protocol to reconstruct resource allocation models (RAMs) by integrating proteomic data. These models were integrated into a unified neuron-astrocyte mouse metabolic model using SteadyCom to simulate metabolic interaction in WT and FABP7 knockout conditions. Resource Balance Analysis (RBA) simulations showed overflow metabolism due to mitochondrial limitations driving the astrocyte-neuron lactate shuttle (ANLS), quantifying their metabolic coupling. We demonstrated that this overflow metabolism further drives the ANLS in TBI due to mitochondrial degradation. Additionally, we found a lack of reactive oxygen species (ROS) scavenging in the FABP7 knockout condition, making damage to the neuron membrane difficult for action potentials to be achieved, thereby decreasing seizure susceptibility. This modeling framework can be extended to investigate metabolism and FABP7-related mechanisms in other neurological disorders.
