TABLE 3.

Effects on synaptic glutamatergic transmission

Contained in this table are synaptic effects other than direct effects on NMDAR function, which are shown in Table 2. Studies and experiments that did not identify an effect are not summarized in this table; please refer to the text for these details.

Concentration/Dose	Timing	Effect	System	References
In vitro or ex vivo application
(2R,6R)-HNK
0.3–30 µM (EC50 = 3.3 µM)	1-h exposure	Increased fEPSP slopea	SC-CA1, rat hippocampal slices	Riggs et al. (2019)
10 µM	1-h exposure			Zanos et al. (2016)
0.3–30 µM (IC50 = 3.8 µM)	1-h exposure	Decreased paired-pulse ratio		Riggs et al. (2019)
10 µM	20-min exposure	Increased sEPSC frequency and amplitude	Rat CA1 stratum radiatum interneurons	Zanos et al. (2016)
10 µM	15- to 25-min exposure	Increased mEPSC frequency (no change in amplitude)	Rat CA1 pyramidal neurons	Riggs et al. (2019)
10 µM	15-min exposure	Increased mEPSC frequency and amplitude	Rat ventrolateral periaqueductal gray neurons	Chou et al. (2018); Ye et al. (2019)
10 µM	1- to 17-min exposure	No change in AMPA-evoked currents	Rat primary cortical neurons	Shaffer et al. (2019)
10 µM	20-min exposure	No change in sEPSC frequency or amplitude	Mouse CA1 interneurons
3–30 µM (EC50 = 7.8 µM)	2-h exposure	No change in baseline fEPSP Slope	SC-CA1, hippocampal slices from 14-day-old mouse	Kang et al. (2020)
		Decreased LTP
(2S,6S)-HNK
10 µM	20-min exposure	No change in sEPSC frequency or amplitude	Rat CA1 interneurons	Zanos et al. (2016)
10 µM	1- to 17-min exposure	No change in AMPA-evoked currents	Rat primary cortical neurons	Shaffer et al. (2019)
1–10 µM (EC50 = 1.0 µM)	2-h exposure	No change in baseline fEPSP Slope	SC-CA1, hippocampal slices from 14-day-old mouse	Kang et al. (2020)
		Decreased LTP
Racemic (2R,6R;2S,6S)-HNK
20 µM	30-min exposure	No change in fEPSP slope	SC-CA1, rat hippocampal slices	Michaelsson et al. (2019)
In vivo administration
10 mg/kg, i.p.	24 h post-treatment	Increased glutamate release	Mouse prefrontal cortex, microdialysis	Pham et al. (2018)
1 nmol/side bilateral intracortical infusion	24 h post-treatment
0.075 mg/kg, i.p.	1 wk post-treatment	Attenuation of AMPAR-mediated EPSC bursts	Mouse hippocampal pyramidal neurons	Chen et al. (2020)
5 mg/kg, i.p.	3.5 h or 1 day post-treatment	Increased magnitude of and slowed decay of LTP	SC-CA1, Wistar-Kyoto stress-susceptible rats, in vivo electrophysiology	Aleksandrova et al. (2020)
10 mg/kg, i.p.	24 h post-treatment	Reversed stress-induced increases in paired-pulse ratios	Rat ventrolateral periaqueductal gray neurons	Chou et al. (2018)
		Reversed stress-induced decreased in inward AMPAR-mediated currents
		Reversed stress-induced decreases in AMPA-evoked currents
		Reversed stress-induced decreases in mEPSC frequency and amplitude
10 mg/kg, i.p.	24 h post-treatment	Increased mEPSC frequency and amplitude	Rat ventrolateral periaqueductal gray neurons	Ye et al. (2019)
		Decreased paired-pulse ratio
		Increased stimulus response relationship
		Increased AMPA-evoked currents
10 mg/kg, i.p.	24 h post-treatment	Decreased mEPSC frequency and amplitude	Mouse dopaminergic ventral tegmental neurons	Yao et al. (2018)
		Decreased AMPAR:NDMAR ratio
		No change in firing frequency
10 mg/kg, i.p.	24 h post-treatment	Decreased LTP	Mouse nucleus accumbens core	Yao et al. (2018)
		No change in stimulus response relation or paired-pulse ratio
30 mg/kg, i.p.	24 h post-treatment	Increased serotonin and hypocretin-evoked sEPSC frequency and amplitude	Mouse prefrontal cortex neurons	Fukumoto et al. (2019)

SC-CA1, Schaffer collateral-CA1 hippocampal synapse; sEPSC, spontaneous excitatory postsynaptic current.

^aShaffer et al. (2019) reported no change in SC-CA1 fEPSP slope after a 1-h exposure to 10 µM (2R,6R)-HNK.