SFN Poster of the Year 2000

Awarded by ATS at Society for Neuroscience (SFN) New Orleans, LA • November 4-9, 2000

389.13 Focal Hippocampal Hyperexcitability After Focal Interneuron Ablation In The Rat By Substance P-Saporin.
J.L. Martin; R.S. Sloviter*, U. Arizona Col. of Med., Tucson, AZ, USA
featuring IT-11 SSP-SAP (Poster)

Hyperexcitability after prolonged seizures or head trauma may result from interneuron malfunction or loss; but a causal relationship is in doubt because global insults produce widespread brain damage and other effects. We have therefore sought to destroy interneurons selectively using stable Substance P-saporin (SSPsap; ATS); a neurotoxin internalized by SP receptor (SPR)-expressing neurons. Improved immunofluorescent methods revealed that most GABA-; parvalbumin (PV)-; and somatostatin (SS)-positive (+) cells of all hippocampal regions (dentate gyrus and areas CA1-CA3) are SPR+; but that granule cells; mossy cells; and CA1-3 pyramidal cells are not. Intrahippocampal injections of SSPsap or vehicle were made under urethane anesthesia in 3 sites (20nl/site) of the dorsal hippocampus of 6 male Sprague-Dawley rats/group. After 5-90 days; rats were blindly evaluated in two sites for CA1 pyramidal cell and dentate granule cell responses to perforant path stimulation (PPS). SSPsap-treated rats exhibited relatively normal responses in some sites; but pathophysiology at other sites that was virtually identical to that seen after prolonged PPS or kainate (multiple population spikes and paired-pulse disinhibition in response to 0.1-2.0Hz perforant path (PP) stimuli). Abnormal responses were observed at the earliest time tested (5 days); and at 90 days. Anatomical analysis revealed selective loss of SPR+; PV+; SS+; and GABA+ neurons; and survival of principal cells and extrinsic afferents. Importantly; "epileptic" pathophysiology was observed exclusively in areas of interneuron loss. These data indicate that the pathophysiology produced by status epilepticus or head trauma can be replicated focally by selective interneuron loss alone; and provide the first direct evidence that highly focal interneuron loss per se is capable of replicating "epileptic" disinhibition and hyperexcitability. In addition; the pathophysiology is restricted to the region of the affected interneuron somata; suggesting a highly localized influence of inhibitory interneurons. Supported by: NIH grant NS18201.