Recruitment of GABAA inhibition in rat neocortex is limited and not NMDA dependent

Abstract

1. The recruitment of evoked fast inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) was examined using whole cell voltage-clamp recordings from layer V pyramidal neurons in slices of rat somatosensory cortex. Synaptic currents were evoked with graded electrical stimulation to assess the relative activation of IPSCs and EPSCs. Fast GABAA ergic IPSCs were selectively recorded by holding cells at potentials equal to EPSC reversal (approximately 0 mV). EPSCs were likewise isolated by holding cells at IPSC reversal potential (about -75 mV). 2. As stimulus intensities were increased, the magnitude of the postsynaptic currents also increased. Over the range of stimuli applied (2-10 V), EPSCs did not exhibit an upper limit. However, fast gamma-aminobutyric acid-A (GABAA-mediated IPSCs reached a maximum at intensities approximately 2 times threshold. 3. The limit on fast inhibition was unresponsive to alterations in N-methyl-D-aspartate (NMDA)-mediated excitation. Exposure to nominally magnesium-free solutions or to the NMDA antagonist 3-[(RS)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid did not affect the fast IPSC maximum. Shifts in the input-output curves for submaximal activation of IPSCs were seen, which were attributed to polysynaptic excitation. 4.Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (non-NMDA) receptors with 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) completely abolished synaptically driven, fast GABAA-mediated inhibition. These findings suggested that neocortical inhibitory cells could be driven exclusively through non-NMDA transmission. 5. By comparison, in hippocampal CA1 pyramidal neurons maximal fast inhibition was sensitive to both NMDA and non-NMDA receptor blockade. 6. The results in neocortex were corroborated by direct intracellular recordings from layer V-VI interneurons. Non-NMDA receptor blockade with CNQX prevented synaptic activation of action potentials in these cells, even during cotreatment with magnesium-free solution. 7. Together, these results suggest that recruitment of GABA(A) ergic IPSCs in neocortex is ultimately driven via glutamatergic afferents arriving at non-NMDA receptors on interneurons. Properties limiting fast inhibition would favor the propagation of enhanced excitatory activity through the neuronal network.

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

“…Differences in postsynaptic responses have in fact been found to be due not only to diversity in postsynaptic specializations, but also to differences in presynaptic properties, indicating that the modulation of transmitter release at pyramidal neuron-interneuron synapses might be far more complex than at a pyramidal-pyramidal neuron connections Deuchars 1994, 1997). It is thought that the glutamatergic receptors involved in these connections are mainly non-NMDA in nature Deuchars 1994, 1997;Ling and Benardo 1995).…”

“…Differences in postsynaptic responses have in fact been found to be due not only to diversity in postsynaptic specializations, but also to differences in presynaptic properties, indicating that the modulation of transmitter release at pyramidal neuron-interneuron synapses might be far more complex than at a pyramidal-pyramidal neuron connections Deuchars 1994, 1997). It is thought that the glutamatergic receptors involved in these connections are mainly non-NMDA in nature Deuchars 1994, 1997;Ling and Benardo 1995).Recent work using laser scanning photostimulation has demonstrated that differences in laminar sources of excitatory input contribute significantly to the diversity of cortical inhibitory interneurons (Dantzker and Callaway 2000). For example, fast-spiking inhibitory basket cells receive strong stimulation from middle cortical layers, while slow firing ones receive their strongest input from deep laminae.…”

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

“…Interneurons express NMDARs, and synaptic NMDARmediated excitatory postsynaptic currents increase robustly between P6 and P8-10 (Zhang and Sun, 2011). Later, interneurons downregulate NMDAR currents (Wang and Gao, 2010), which could explain why NMDARs play no role in the recruitment of feed-forward inhibition by adult thalamocortical inputs (Hull et al, 2009;Ling and Benardo, 1995). A recent study shows that depleting the GluN1 subunit from postnatal corticolimbic interneurons causes a schizophrenia-like phenotype, with a loss of Gad67 and parvalbumin expression and deficits in inhibition (Belforte et al, 2010).…”

Synaptic Contributions to Focal and Widespread Spatiotemporal Dynamics in the Isolated Rat SubiculumIn Vitro

“…This would allow detection of formerly hidden functional circuits. Additionally, in the zero Mg 2ϩ model (1) recurrent inhibition is not directly impaired (Ling and Benardo, 1995), and (2) NMDA receptors contribute a small tonic depolarizing current that inject firing into the network (LoTurco et al, 1990;Myme et al, 2003). We also tested the effect of increasing cell excitability under 5 mM K ϩ and the possible developmental changes.…”