Hashimotodani, Y. | bioRxiv Science

bioRxiv2024

Distinct release properties of glutamate/GABA co-transmission serve as a frequency-dependent filtering of supramammillary inputs

Glutamate and GABA co-transmitting neurons exist in several brain regions; however, the mechanism by which these two neurotransmitters are co-released from the same synaptic terminals remains unclear. Here, we show that the supramammillary nucleus (SuM) to dentate granule cell synapses, which co-release glutamate and GABA, exhibit differences between glutamate and GABA release properties in paired-pulse ratio, Ca2+-sensitivity, presynaptic receptor modulation, and Ca2+ channel-vesicle coupling configuration. Moreover, uniquantal synaptic responses show independent glutamatergic and GABAergic responses. Morphological analysis reveals that most SuM terminals form distinct glutamatergic and GABAergic synapses in proximity, each characterized by GluN1 and GABAA1 labeling, respectively. Notably, glutamate/GABA co-transmission exhibits distinct short-term plasticities, with frequency-dependent depression of glutamate and frequency-independent stable depression of GABA. Our findings suggest that glutamate and GABA are co-released from different synaptic vesicles within the SuM terminals, and reveal that distinct transmission modes of glutamate/GABA co-release serve as frequency-dependent filters of SuM inputs.

neuroscience↗

bioRxiv2021

Retrograde adenosine/A2A receptor signaling mediates presynaptic hippocampal LTP and facilitates epileptic seizures

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity. HighlightsO_LIPostsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses C_LIO_LIPostsynaptic TrkB activation induces adenosine release from granule cells C_LIO_LIPresynaptic adenosine A2A receptors are necessary and sufficient to induce LTP C_LIO_LIAdenosine/A2AR signaling within the dentate gyrus is pro-convulsant C_LI In BriefNasrallah et al. report a novel retrograde signaling pathway at hippocampal synapses that involves postsynaptic TrkB-dependent release of adenosine and the activation of presynaptic A2A receptors. This pathway mediates presynaptic long-term potentiation at a key hippocampal excitatory synapse and can also promote epileptic seizures.

neuroscience↗