Ingebretsen, E. A. | bioRxiv Science

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↗

bioRxiv2023

Inhibition of noradrenaline-dependent synaptic transmission in the dorsal raphe nucleus by alpha2-adrenergic receptors

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory 1-adrenergic receptors (1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an 1-AR-mediated excitatory postsynaptic current (1-AR-EPSC). Activation of inhibitory 2-adrenergic receptors (2-AR) with UK-14,304 eliminated the 1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic 2-AR produced an outward current through activation of potassium conductance. Further, in vivo activation of 2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, 2-AR are critical regulators of serotonin neuron excitability.

neuroscience↗