Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.

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Pentameric GABAA receptors are composed from 19 possible subunits. The GABAA β subunit is unique because the β1 and β3 subunits can assemble and traffic to the cell surface as homomers, whereas most of the other subunits, including β2, are heteromers. The intracellular domain (ICD) of the GABAA subunits has been implicated in targeting and clustering GABAA receptors at the plasma membrane. Here, we sought to test whether and how the ICD is involved in functional expression of the β3 subunit. Since θ is the most homologous to β but does not form homomers, we created two reciprocal chimeric subunits, swapping the ICD between the β3 and θ subunits, and expressed them in HEK293 cells. Surface expression was detected with immunofluorescence and functional expression was quantified using whole-cell patch-clamp recording with fast perfusion. Results indicate that, unlike β3, neither the β3/θIC nor the θ/β3IC chimera can traffic to the plasma membrane when expressed alone; however, when expressed in combination with either wild-type α3 or β3, the β3/θIC chimera was functionally expressed. This suggests that the ICD of α3 and β3 each contain essential anterograde trafficking signals that are required to overcome ER retention of assembled GABAA homo- or heteropentamers.