Long-term plasticity at inhibitory synapses

Abstract

Experience-dependent modifications of neural circuits and function are believed to heavily depend on changes in synaptic efficacy such as LTP/LTD. Hence, much effort has been devoted to elucidating the mechanisms underlying these forms of synaptic plasticity. Although most of this work has focused on excitatory synapses, it is now clear that diverse mechanisms of long-term inhibitory plasticity have evolved to provide additional flexibility to neural circuits. By changing the excitatory/inhibitory balance, GABAergic plasticity can regulate excitability, neural circuit function and ultimately, contribute to learning and memory, and neural circuit refinement. Here we discuss recent advancements in our understanding of the mechanisms and functional relevance of GABAergic inhibitory synaptic plasticity.

Figure 1. Molecular mechanisms underlying presynaptic forms of GABAergic plasticity following repetitive afferent activity

A. eCB-mediated I-LTD mediated is triggered by postsynaptic activation of group I metabotropic glutamate receptors (mGluR-I), leading to the production of diacylglyercol (DAG) by phospholipase C (PLC). Diacylglycerol lipase (DGL) converts DAG to the major eCB, 2-AG, which is released from the postsynaptic cell and travels back across the synapse to activate type 1 cannabinoid receptors (CB1Rs) on the GABAergic terminal. CB1R activation subsequently reduces protein kinase A activity. Coincident interneuronal activity increases intracellular calcium via voltage-gated calcium channels (VGCCs) and enhances calcineurin (CaN) activity. Combined reduction and enhancement of PKA and CaN activity, respectively, may lower the phosphorylation status of an unidentified substrate in the release machinery to persistently depress GABA release in a Rim1α-dependent manner. B. I-LTP mediated by brain-derived neurotrophic factor (BDNF) is initiated by intracellular calcium rise due to opening of either NMDARs or VGCCs, or calcium release from intracellular stores, depending on the synapse and brain region. Postsynaptic GABA_BR activation reportedly can lead to calcium release from stores via an unknown mechanism. BDNF acts as a retrograde messenger to activate TrkB receptor tyrosine kinases on the inhibitory terminal to potentiate GABA release through an unclear pathway. C. I-LTP mediated by nitric oxide (NO) is induced by intracellular calcium rise in the postsynaptic cell via opening of NMDARs to activate nitric oxide synthase (NOS). NO readily permeates through the membrane and stimulates presynaptic guanylate cyclase (GC), augmenting cGMP levels to enhance GABA release. Mu-opioid receptors (μORs) antagonize the ability of NO to increase cGMP signaling. D. Glutamate (Glu) can also directly activate presynaptic NMDARs on the GABAergic interneuron, without the need for retrograde messengers. Depending on the synapse, calcium increase at the terminals can depress GABA release through uncharacterized mechanisms or potentiate GABA release in a PKA- and RIM1α-dependent manner.

Figure 2. Cellular expression mechanisms underlying postsynaptic forms of GABAergic plasticity

Left, the concentration of ions inside the cell may change as a result in an enhancement in transporter activity following induction of plasticity. Intracellular chloride is high due to import activity of NKCC1 in the immature brain and is low due to the extrusion activity of KCC2 in the mature brain [82]. Activity can couple to changes in chloride transporter function, possibly through direct phosphorylation of the chloride transporters or by inducing trafficking-mediated changes in surface transporter levels. The altered chloride transported function results in a change in the driving force for chloride and consequently amplitude of GABA_AR-mediated responses. Middle, changes in receptor function may occur as a result of direct phosphorylation by kinases including protein kinase C (PKC), calmodulin-kinase II (CaMKII), PKA or Src, or dephosphorylation by CaN [54,70]. Right, the number of GABA_ARs may change due to receptor trafficking regulation. Inhibitory responses can decrease as a result of enhanced endocytosis, or increase due to enhanced exocytosis [87]. Ubiquitination of the receptor can reduce the stability of receptors in the ER resulting in a decrease in receptor insertion [79].