Abstracts

Rationale: Low-threshold spiking (LTS) but not fast-spiking neocortical interneurons are excited by Group I metabotropic glutamate receptor (mGluR) agonists. Rhythmic spiking in LTS cells during mGluR application synchronizes the activity of surrounding pyramidal neurons. We hypothesize that LTS cells are altered in number or function in the freeze-lesion model of microgyria, creating a hyper-synchronous cortical state in the epileptogenic paramicrogyral area (PMG). Our preliminary whole cell patch clamp data show that application of the mGluR type I agonist, (S)-3,5-Dihydroxyphenylglycine hydrate (DHPG) produces a significantly larger increase in sIPSC frequency in PMG compared to control layer V pyramidal neurons (George & Jacobs 2007 SFN abstract). This suggests that PMG interneurons are either more sensitive to DHPG or are increased in number. Here we have examined the effects of mGluR agents on the cortical network using field potential recordings.Methods: Transcranial freeze lesions over somatosensory cortex were made in rats on postnatal day (P) 1. Coronal slices were taken on P13-19. Field potential recordings were made simultaneously in superficial (SF) and deep layers (DF) in the cortical column above the stimulating electrode within layer VI, ~1 mm from the sulcus, or in homologous control cortex from unlesioned rats. Fields were evoked at a mid-range intensity, 1/30 sec, and averaged over 2.5 min epochs. Drugs were applied in the aCSF at the following concentrations: 10 μM DHPG; 30 μM 1-Amino-2,3-dihydro-1H-indene-1,5-dicarboxylic acid (AIDA); 10 μM 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Measures of the field potential after 30-40 minutes of application were compared within each slice to predrug conditions and are reported as % change±SEM.Results: In 6 control slices, DHPG decreased the peak, and increased the area and halfwidth of the SF (-14±8%; 68±49%; 15±12%, t-test, p<0.05) but decreased the peak and area of the DF (-28±11%; -27±14%, t-test, p<0.05). In 6 PMG slices, the SF showed no change in peak or area, and a small increase in halfwidth (11±11%, N.S.; 7±6%, p<0.05). In striking contrast to control cortex, the PMG DF showed no change in peak but a 112±58% increase in area and a 34±29% increase in halfwidth (p<0.05). Application of the mGluR5 selective antagonist, MPEP did not affect any of the fields in either PMG or control cortex (12 slices each). The mGluR1 selective antagonist, AIDA produced effects opposite to DHPG in 14 control slices: (SF peak 9±5%, DF peak 6±3%, DF area 33±13%, t-tests, p<0.05), and 18 PMG slices (DF area -14±7, t-test, p<0.05).Conclusions: The deep layers of PMG cortex respond to mGluR agonists similar to the superficial layers of control cortex and significantly different from the control deep layers (t-test, p<0.05). Thus, there is an increased sensitivity to mGluR type I agonists in deep PMG cortex, and perhaps an decreased sensitivity in superficial PMG cortex. This may arise from an abnormal distribution of interneurons containing mGluR receptors within malformed epileptogenic cortex. (Supported by the Epilepsy Foundation)