Plasticity of rat central inhibitory synapses through GABA metabolism

Abstract

The brain adapts to experience by changing synaptic efficacy. Extensively studied mechanisms of plasticity include changes in the probability of transmitter release and in postsynaptic responsiveness. However, evidence from aminergic synapses indicates that the biochemistry of neurotransmitters provides an additional tool to alter synaptic strength. For example, dopaminergic transmission can be boosted by the precursor L-DOPA, which enhances the transmitter content of individual vesicles (Pothos et al. 1996) and counteracts Parkinson's disease.A similar principle may apply to one of the major central transmitters, the inhibitory amino acid GABA (y-aminobutyric acid). Drugs enhancing the tissue content of GABA act as anticonvulsants (Löscher et al. 1989; Taylor et al. 1992), suggesting that inhibitory tone depends on GABA supply. Moreover, the production of endogenous GABA varies, depending on the functional needs of the network: gonadotropin secretion from hypothalamic neurons is regulated through the negative feedback of gonadal steroids on the activity of the GABAproducing enzyme glutamate decarboxylase (GAD; Grattan et al. 1996); in hippocampal interneurons, suppression of GAD expression by oestradiol results in decreased inhibition and subsequent changes in dendritic spine 1. The production of the central inhibitory transmitter GABA (y-aminobutyric acid) varies in response to different patterns of activity. It therefore seems possible that GABA metabolism can determine inhibitory synaptic strength and that presynaptic GABA content is a regulated parameter for synaptic plasticity.2. We altered presynaptic GABA metabolism in cultured rat hippocampal slices using pharmacological tools. Degradation of GABA by GABA-transaminase (GABA-T) was blocked by y-vinyl-GABA (GVG) and synthesis of GABA through glutamate decarboxylase (GAD) was suppressed with 3-mercaptopropionic acid (MPA). We measured miniature GABAergic postsynaptic currents (mIPSCs) in CA3 pyramidal cells using the whole-cell patch clamp technique.3. Elevated intra-synaptic GABA levels after block of GABA-T resulted in increased mIPSC amplitude and frequency. In addition, tonic GABAergic background noise was enhanced by GVG. Electron micrographs from inhibitory synapses identified by immunogold staining for GABA confirmed the enhanced GABA content but revealed no further morphological alterations.4. The suppression of GABA synthesis by MPA had opposite functional consequences: mIPSC amplitude and frequency decreased and current noise was reduced compared with control. However, we were unable to demonstrate the decreased GABA content in biochemical analyses of whole slices or in electron micrographs.5. We conclude that the transmitter content of GABAergic vesicles is variable and that postsynaptic receptors are usually not saturated, leaving room for up-regulation of inhibitory synaptic strength. Our data reveal a new mechanism of plasticity at central inhibitory synapses and provide a rationale for the activity-dependent regulation of GABA synthesis in ...

Inhibition of GABA release by presynaptic ionotropic GABA receptors in hippocampal CA3

“…Several different mechanisms may explain this apparent discrepancy: presynaptic GABA receptors may be differentially expressed in different preparations and, most importantly, chloride extrusion mechanisms may differ [21]. There are also several experimental differences between the work by Engel et al [9] and our present approach, most notably the time of incubation. Indeed, the acute and long-term effects of vigabatrin may differ, causing even pro-convulsant effects of this anticonvulsant drug at early stages after application [22].…”

“…5), vigabatrin suppressed both stimulus-evoked and miniature IPSCs. In a previous study, however, we had found an increased, rather than decreased, frequency of mIPSCs in cultured hippocampal slices after long-term incubation with vigabatrin [9]. Several different mechanisms may explain this apparent discrepancy: presynaptic GABA receptors may be differentially expressed in different preparations and, most importantly, chloride extrusion mechanisms may differ [21].…”

“…Consistent with this idea, several recent studies have reported that changes in presynaptic GABA content cause alterations of the actionpotential-dependent and -independent release of GABA. These changes implicate a negative [5,7,8] or positive [9][10][11] correlation between presynaptic GABA content and vesicular release of GABA. Indeed, GABA can yield opposite effects on transmitter release at different synapses, i.e.…”

Homeostatic Scaling of Vesicular Glutamate and GABA Transporter Expression in Rat Neocortical Circuits

“…The latter can be achieved by scaling the amount of vesicular transporter protein per vesicle, which increases or decreases the vesicular loading capacity and thereby regulates the quantal size of transmitter release (Wilson et al, 2005). Alterations in the cytoplasmic levels of glutamate and GABA available for vesicular sequestration also result in corresponding changes in vesicular storage and release (Engel et al, 2001;Yamashita et al, 2003). The set point of synaptic vesicle glutamate and GABA storage might therefore be controlled by the number of functional transporters and the cytoplasmic transmitter concentration (Wilson et al, 2005) similarly to that described for the vesicular acetylcholine transporter after heterologous gene expression Erickson, 1996, 1997), supporting a steady-state equilibrium model of vesicle transmitter packet size (Williams, 1997).…”

“…At central glutamatergic and GABAergic terminals, synaptic vesicles may not be filled to their maximal capacity (Engel et al, 2001;Yamashita et al, 2003), and release from single vesicles is not enough to saturate postsynaptic receptors at some synapses (Liu et al, 1999;Hajos et al, 2000;McAllister and Stevens, 2000;Ishikawa et al, 2002). Therefore, variability in the amount of transmitter loaded into vesicles at central excitatory and inhibitory synapses could significantly contribute to endogenous variations in quantal release measured in cultured neurons (Frerking et al, 1995;Liu et al, 1999) and in synaptic transmission.…”