Delivery of graphene oxide nanosheets modulates glutamate release and normalizes amygdala synaptic plasticity to improve anxiety-related behavior.

Graphene oxide nanosheets (GO) were reported to alter neurobiological processes involving cell membrane dynamics. GO ability to reversibly downregulate specifically glutamatergic synapses underpins their potential in future neurotherapeutic developments. Aberrant glutamate plasticity contributes to stress-related psychopathology and drugs which target dysregulated glutamate represent promising treatments. We find that in a rat model of post-traumatic stress disorder (PTSD), a single injection of GO to the lateral amygdala following the stressful event induced PTSD-related behavior remission and reduced dendritic spine densities. We explored from a mechanistic perspective how GO could impair glutamate synaptic plasticity. By simultaneous patch clamp pair recordings of unitary synaptic currents, live-imaging of presynaptic vesicle release and confocal microscopy, we report that GO nanosheets altered the probability of release enhancing the extinction of synaptic plasticity in the amygdala. These findings show that the modulation of presynaptic glutamate release might represent an unexplored target for (nano)pharmacological interventions of stress-related disorders.

Graphene oxide prevents lateral amygdala dysfunctional synaptic plasticity and reverts long lasting anxiety behavior in rats.

Engineered small graphene oxide (s-GO) sheets were previously shown to reversibly down-regulate glutamatergic synapses in the hippocampus of juvenile rats, disclosing an unexpected translational potential of these nanomaterials to target selective synapses in vivo. Synapses are anatomical specializations acting in the Central Nervous System (CNS) as functional interfaces among neurons. Dynamic changes in synaptic function, named synaptic plasticity, are crucial to learning and memory. More recently, pathological mechanisms involving dysfunctional synaptic plasticity were implicated in several brain diseases, from dementia to anxiety disorders. Hyper-excitability of glutamatergic neurons in the lateral nucleus of the amygdala complex (LA) is substantially involved in the storage of aversive memory induced by stressful events enabling post-traumatic stress disorder (PTSD). Here we translated in PTSD animal model the ability of s-GO, when stereotaxically administered to hamper LA glutamatergic transmission and to prevent the behavioral response featured in long-term aversive memory. We propose that s-GO, by interference with glutamatergic plasticity, impair LA-dependent memory retrieval related to PTSD.