Modulation of GABAergic and glutamatergic transmission by ethanol in the developing neocortex: an in vitro test of the excessive inhibition hypothesis of fetal alcohol spectrum disorder.

Exposure to ethanol during development triggers neuronal cell death and this is thought to play a central role in the pathophysiology of fetal alcohol spectrum disorder (FASD). Studies suggest that ethanol-induced neurodegeneration during the period of synaptogenesis results from widespread potentiation of GABA(A) receptors and inhibition of NMDA receptors throughout the brain, with neocortical layer II being particularly sensitive. Here, we tested whether ethanol modulates the function of these receptors during this developmental period using patch-clamp electrophysiological and Ca(2+) imaging techniques in acute slices from postnatal day 7-9 rats. We focused on pyramidal neurons in layer II of the parietal cortex (with layer III as a control). Ethanol (70mM) increased spontaneous action potential-dependent GABA release in layer II (but not layer III) neurons without affecting postsynaptic GABA(A) receptors. Protein and mRNA expression for both the Cl(-) importer, NKCC1, and the Cl(-) exporter, KCC2, were detected in layer II/III neurons. Perforated-patch experiments demonstrated that E(Cl)((-)) is shifted to the right of E(m); activation of GABA(A) receptors with muscimol depolarized E(m), decreased action potential firing, and minimally increased [Ca(2+)](i). However, the ethanol-induced increase of GABAergic transmission did not affect neuronal excitability. Ethanol had no effect on currents exogenously evoked by NMDA or AMPA receptor-mediated spontaneous excitatory postsynaptic currents. Acute application of ethanol in the absence of receptor antagonists minimally increased [Ca(2+)](i). These findings are inconsistent with the excessive inhibition model of ethanol-induced neurodegeneration, supporting the view that ethanol damages developing neurons via more complex mechanisms that vary among specific neuronal populations.

Facilitated glutamate release at Schaffer collateral to CA1 synapses has access to an exclusive population of NMDA receptors.

In order to explore short-term facilitation of the Schaffer collateral to CA1 synapse in mouse hippocampal brain slices, we measured the time course of the decay of the peak amplitude of successive EPSCs during progressive MK-801-dependent block (PMDB) of NMDAR responses to paired (R1 and R2) stimuli. We made the unexpected observation that the R2 response exhibited a slower PMDB decay constant than that of the R1 response. This indicated that the facilitated R2 response engages release sites with NMDARs that are protected from opening and consequent MK-801 block during the basal R1 response. We then utilized conditions that affect synaptic glutamate distribution to dissect the components of the distinct PMDB decay constants of the first and second of paired pulses. While extra-synaptic NMDARs and glutamate transporters appear to play only minor roles in the differences of the PMDB decay constant, we showed important roles for the R1 response itself and for glutamate diffusion in determining the PMDB decay constant of R2. We used a simple computational model with realistic parameters that allowed us to predict the time course of R2 decay based on the R1 decay time course.

Induction frequency affects cortico-striatal synaptic plasticity with implications for frequency filtering.

Long-term synaptic depression (LTD) in cortico-striatal circuits is initiated by depolarization of striatal medium spiny neurons through a convergent cortical glutamatergic input. This produces retrograde endocannabinoid signaling to presynaptic cortical terminals and eventually results in long term (>30 min) decreases in glutamate release. These same circuits can also undergo short-term depression (STD) through a less well-defined process in which the magnitude of postsynaptic responses returns to baseline levels within 10 min. Additionally, the cortico-striatal circuit shows characteristics of a GABAA receptor-dependent low-pass filter, which results in significant attenuation of high frequency cortical inputs. The majority of in vitro studies of LTD have used a 100-Hz induction paradigm and it is unclear whether other frequencies, which may also have physiological relevance, have equivalent ability to induce this form of plasticity. Here we have investigated the effectiveness of a range of induction paradigms in producing LTD in cortico-striatal circuits, and demonstrate that some lower frequency paradigms, with perhaps more physiological relevance, are more effective at inducing LTD. We also show that GABAA receptor-dependent frequency filtering in this circuit is altered following the induction of LTD and STD suggesting an important role for synaptic depression in signal processing in these circuits.