Hippocampal GABAergic transmission: a new target for adenosine control of excitability

Abstract

Physiological network functioning in the hippocampus is dependent on a balance between glutamatergic cell excitability and the activity of diverse local circuit neurons that release the inhibitory neurotransmitter c-aminobutyric acid (GABA). Tuners of neuronal communication such as adenosine, an endogenous modulator of synapses, control hippocampal network operations by regulating excitability. Evidence has been recently accumulating on the influence of adenosine on different aspects of GABAergic transmission to shape hippocampal function. This review addresses how adenosine, through its high-affinity A 1 (A 1 R) and A 2A receptors (A 2A R), interferes with different GABA-mediated forms of inhibition in the hippocampus to regulate neuronal excitability. Adenosinemediated modulation of phasic/tonic inhibitory transmission, of GABA transport mechanisms and its interference with other modulatory systems are discussed together with the putative implications for neuronal function in physiological and pathological conditions.

Expression of functional inhibitory neurotransmitter transporters GlyT1, GAT-1, and GAT-3 by astrocytes of inferior colliculus and hippocampus

“…Mixed inhibitory synaptic transmission, with co-release of glycine and GABA from the same presynaptic terminal, takes place in various caudal brain regions, such as auditory brainstem, ventral respiratory group, cerebellum, and spinal cord [ 1 – 8 ]. In more rostral brain regions, like the hippocampus (HC), GABA is utilized for inhibitory synaptic transmission [ 9 , 10 ], while glycine co-released from glutamatergic terminals can modulate NMDA receptor (NMDAR)-mediated signaling [ 11 , 12 ]. Accordingly, glycine transporters (GlyTs) and GABA transporters (GATs) are widely expressed in astrocytes and neurons [ 13 – 16 ] to enable neurotransmitter clearance, reuptake, and modulation of neuronal signaling [ 15 , 17 , 18 ].…”

“…2) The HC is the second system of interest. Whereas its main circuitry is glutamatergic [ 35 , 36 ], inhibitory synaptic transmission arises from GABAergic interneurons [ 9 , 10 ]. In line with this, astrocytes in the stratum radiatum express GAT-3, whereas GAT-1 has been attributed to interneurons [ 21 , 37 ].…”

On the role of stigmergy in cognition

“…Their action occurs within a time frame of milliseconds to seconds. A well known example of neuromodulador is adenosine (Dias et al, 2013), (Sebastião and Ribeiro, 2015) and (Rombo et al, 2016), whose membrane receptors are the targets of caffeine (Ribeiro and Sebastião, 2010). Other well known examples are endocannabinoids (Katona and Freund, 2012), whose membrane receptors are the targets of cannabis (Solymosi and Köfalvi, 2016).…”

7thISN special neurochemistry conference ‘Synaptic function and dysfunction in brain diseases’

“…The modulation of GABAergic neurotransmission by adenosine receptors, under normal physiological conditions and in pathological conditions, with an impact in the regulation of neuronal excitability, is discussed by Rombo et al . ().…”

“…The review by Cunha (2016) focuses on how adenosine controls neuronal function and dysfunction, and is implicated in neurodegeneration by regulating neuronal, astrocytical and microglia activity, and suggests that targeting adenosine inhibitory (A 1 R) and excitatory (A 2 R) receptors may be an effective neuroprotection strategy. The modulation of GABAergic neurotransmission by adenosine receptors, under normal physiological conditions and in pathological conditions, with an impact in the regulation of neuronal excitability, is discussed by Rombo et al (2016).…”