Abstracts

Rationale: Polymicrogyria is a developmental disorder of the neocortex that is associated with epilepsy. The paramicrogyral region (PMG) in clinical and experimental microgyria exhibits abberrant electrophysiological properties and protein expression patterns. Epileptiform discharges can readily be evoked from this region. We assessed the role of AMPA and GABA-A receptor mediated synaptic transmission in PMG hyperexcitability following freeze-lesions in the primary somatosensory cortex in rats.Methods: We used laser scanning photostimulation to map the extent and strength of excitatory (AMPA receptor mediated) and inhibitory (GABA-A receptor mediated) connectivity onto layer 2/3 and layer 5 pyramidal neurons in PMG and control cortex of rats aged P16 to P20. Excitatory and inhibitory connectivity maps were recorded from the same neurons by using different holding potentials (-60 mV, chloride equilibrium potential, for excitatory mapping; -5 mV, near the cation equilibrium potential, for inhibitory mapping), allowing for pairwise comparisons. We also assessed presynaptic (release probability) and postsynaptic (rectification) function of AMPA receptor mediated responses using standard electrical stimulation protocols.Results: In PMG pyramidal neurons, monosynaptic EPSCs could be evoked from a wider area during laser scanning photostimulation than in control neurons. Specifically, layer 2/3 neurons received significantly more synaptic input from deep layers, while layer 5 pyramidal cells received more input from superficial layers. Intralaminar connecticity was also increased, but not to the level of statistical significance. Amplitude and kinetics of evoked EPSCs, however, were indistinguishable. GABA-A receptor mediated connectivity between pyramidal cells and local interneurons did not differ significantly between PMG and control pyramidal cells. Pairwise comparisons of overall excitatory and inhibitory connectivity in individual pyramidal neurons demonstrated a significant increase in the relative strength of excitatory connectivity in PMG neurons. In the PMG, EPSCs evoked by electrical stimulation were inwardly rectifying, indicating that they were mediated in large part by GluR2-lacking, calcium permeable AMPA receptors. EPSCs in control neurons had linear current/voltage relationships, indicative of GluR2-containing AMPA receptors. Presynaptic release probability was largely unaffected in PMG neurons.Conclusions: We demonstrate a specific increase in excitatory connection probability in the hyperexcitable PMG along the canonical neocortical projection pathways (layer 4 to layer 2/3 to layer 5). A significant proportion of AMPA receptors along these projections was GluR2-lacking, which will allow for increased calcium influx into PMG pyramidal neurons. Both effects would work in concert to contribute to tissue hyperexcitability and epilepsy.