The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Abstract

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.

The effects of social isolation stress and discrimination on mental health

“…Glutamate and GABA are the main neurotransmitters regulating excitation and inhibition in the human brain [ 59 ], as also evinced by human imaging studies [ 60 ]. Stress exposure has been suggested to impair neuronal integrity of excitatory glutamate neurons and inhibitory GABA interneurons in limbic and cortical brain areas also implicated in major affective disorders [ 61 ].…”

GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity

“…Recent studies, using genetically targeted recordings, enabled an insight into the mechanisms whereby distinct interneurons participate in the formation of hippocampal memory 5,6 . This expanding knowledge on GABAergic inhibition encouraged a more "holistic" approach considering additionally plasticity at GABAergic synapses and its interplay with the glutamatergic drive [8][9][10][11] . Consequently, in the past decade or so, GABAergic inhibition was shown to undergo many forms of plasticity and the underlying molecular mechanisms start to be unraveled 8 .…”

“…This expanding knowledge on GABAergic inhibition encouraged a more "holistic" approach considering additionally plasticity at GABAergic synapses and its interplay with the glutamatergic drive [8][9][10][11] . Consequently, in the past decade or so, GABAergic inhibition was shown to undergo many forms of plasticity and the underlying molecular mechanisms start to be unraveled 8 . In particular, we have recently shown that stimulation of transmembrane adhesion molecules, integrins with specific peptides induced different types of GABAergic plasticity in the hippocampus 12 while Kawaguchi and Hirano (2006) reported that α3β1 integrin suppressed long-term potentiation at inhibitory synapses on the cerebellar Purkinje neurons.…”

Recent advances in understanding neuronal diversity and neural circuit complexity across different brain regions using single-cell sequencing

“…To this end, significant diversity in excitatory and inhibitory neurons in the cerebral cortex revealed by single-cell sequencing will be discussed. Glutamatergic neurons, as the most common and widely studied excitatory neurons in cortical circuits, have important molecular signatures and specific physiological properties ( Birey et al, 2017 ; Chapman et al, 2022 ; Zhong et al, 2022 ). This importance also holds true for GABAergic neurons in inhibitory circuits and long-range projections ( Rock et al, 2017 ; Kirmse and Zhang, 2022 ).…”