AUTAPTIC SELF-INHIBITION OF PARVALBUMIN INTERNEURONS DRIVES NETWORK HYPEREXCITABILITY IN GABAA RECEPTOR GAIN-OF-FUNCTION ENCEPHALOPATHY

Pathogenic variants in genes encoding GABA_A receptors lead to severe developmental and epileptic encephalopathies. In patients, nearly half of these variants result in gain-of-function (GOF) mutations, while the remainder lead to loss-of-function (LOF) effects. Given that epilepsy is canonically linked with excessive excitation or reduced inhibition, it is paradoxical that GOF mutations – expected to enhance inhibition - lead to earlier seizure onset and increased symptom severity. Moreover, patients with GOF variants are frequently resistant to standard antiseizure medications. The mechanism by which enhanced GABA_A receptor activity leads to hyperexcitability remains unclear.
Using a GOF mouse model carrying a missense mutation in the GABA_A β3 subunit (Gabrb3 E77K), we found that feedforward inhibition (FFI) in the somatosensory cortex undergoes a developmental switch. In young animals, FFI was increased, consistent with enhanced receptor function. In contrast, in adult animals, FFI was unexpectedly and strongly reduced. Paired recordings between parvalbumin-positive (PV+) interneurons and pyramidal cells showed no alteration in monosynaptic inhibitory strength, suggesting an alteration in circuit-level organization. In support, we identified an increase in the prevalence of autaptic self-inhibiting connections in PV+ interneurons. Enhanced autaptic inhibition likely suppresses PV+ neuron excitability, thereby shifting the cortical network toward excess excitation. Together, these findings establish a paradoxical developmental loss in cortical inhibition in a GABA_A receptor GOF mouse model and implicate elevated autaptic inhibition as a circuit-level mechanism of disinhibition contributing to hyperexcitability. These results suggest that therapeutic intervention may be most effective early in development, before maladaptive network reorganization becomes established.