Biology subjects

Fong, T. H.

Publications and source records attributed to Fong, T. H..

3 recordsLinked to original sources

bioRxiv2026

Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine's metabolite

A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamines antidepressant efficacy, yet their precise contributions remain poorly understood. Here, we demonstrate that one major metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets -{delta} opioid receptor heterodimers (-{delta}-ORs) on astrocytes. By promoting the formation and/or stabilization of -{delta}-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca{superscript 2} dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting -{delta}-OR assembly or Gs signaling abolishes HNK-mediated antidepressant responses both in vitro and in vivo. Collectively, astrocytic opioid receptor heterodimers are critical to antidepressant responses and HNK may serve as a prototype compound for targeting astrocyte dysfunction across a wide range of brain disorders.

neuroscience↗

bioRxiv2026

(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both {micro}- and {delta}-opioid receptors in astrocytes. Chronic stress reduces {micro}-{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased {micro}-{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the {micro}-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic {micro}-{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.

neuroscience↗

bioRxiv2024

Key contribution of prefrontal inhibition to passive coping behaviour: chronic stress and fast-acting antidepressant

Persistent passive coping behaviour is a hallmark feature in major depression and is reversed by fast-acting antidepressants (such as ketamine). This behaviour is regulated by a specific cortico-midbrain circuit. However, whether the prefrontal cortex (PFC), especially inhibition in PFC, contributes to the modulation of passive coping, and whether this modulation is important for mediating the impacts of chronic stress and/or fast-acting antidepressants, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls the occurrence of passive coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to reduced excitation/inhibition (E/I) ratio, reflected as alterations in in vivo spiking rate, synaptic inputs and intrinsic excitability of both excitatory and inhibitory neurons. A fast-acting antidepressant, (2R, 6R)-hydroxynorketamine (HNK), reduced passive coping behaviour, restored rPL E/I ratio and partially reversed altered properties in rPL neurons, in chronically stressed mice. Importantly, chronic stress and HNK mostly affected fast-spiking/parvalbumin inhibitory neurons instead of other inhibitory neurons, indicating the important role of this subtype of inhibitory neurons in the above processes. These findings demonstrate the importance of rPL E/I balance in regulating passive coping, which can be modulated by chronic stress and rapidly restored by fast-acting antidepressant.

neuroscience↗