Atack, J. R. | Search bioRxiv

bioRxiv2026

Negative allosteric modulation of α5-GABAA receptors engages dynamic cortical glutamatergic and GABAergic mechanisms underlying adaptive behavior in mice

Chronic stress disrupts glutamatergic and GABAergic plasticity in the medial prefrontal cortex (mPFC), impairing circuit integration and contributing to the pathophysiology of stress-related disorders, such as Major Depressive Disorder (MDD). Rapid-acting antidepressants like ketamine can rapidly reverse these deficits, but its clinical use is limited by psychotomimetic side effects. Notably, the 5-GABAAR negative allosteric modulator (5-NAM) Basmisanil (BSM), reproduces ketamine-like behavioral outcomes in preclinical models, although the cellular mechanisms underlying its actions remain unclear. Here, we investigated whether BSM promotes ketamine-like enhancement of cortical plasticity and engages cell type-specific mechanisms to support adaptive behaviors over time. We show that BSM produced rapid and sustained facilitation of motivational, hedonic, and active coping behaviors via mPFC circuits. BSM induced c-Fos expression in mPFC D1R- and somatostatin-expressing cells, suggesting activation of specific subsets of pyramidal and GABA interneurons. In both mPFC and hippocampus, BSM rapidly activated Erk- or Akt-mTOR signaling pathways as well as increased synaptic proteins critical for glutamatergic and GABAergic function. BSM also reversed maladaptive behaviors induced by chronic unpredictable stress, including impairment in object recognition memory and social interaction. Finally, chemogenetic silencing of mPFC CaMKII-expressing neurons blocked both rapid and sustained actions of BSM, whereas inhibition of mPFC GABA interneurons reversed only long-term behavioral outcomes. These results indicate that 5-GABAAR modulation requires early activation of pyramidal neurons to drive rapid plasticity, while GABAergic adaptations support sustained improvements. This dynamic mechanism restores excitation-inhibition (E/I) balance and highlights GABAergic pathways as therapeutic targets for prefrontal dysfunction in stress disorders.

pharmacology and toxicology↗

bioRxiv2021

Tyrosine 121 moves revealing a druggable pocket that couples catalysis to ATP-binding in serine racemase

Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a closed hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the ATP a-phosphate. In contrast, in open hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzymefragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.

biophysics↗