title: Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor.
abstract: Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments.
authors.affiliation: Department of Psychology, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Botterill
authors.affiliation: Department of Psychology, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Guskjolen
authors.affiliation: Department of Psychology, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada.
authors.forename: W N
authors.initials: WN
authors.lastname: Marks
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, S7N 5A5, Canada.
authors.forename: H J
authors.initials: HJ
authors.lastname: Caruncho
authors.affiliation: Department of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada. lisa.kalynchuk@usask.ca.
authors.forename: L E
authors.initials: LE
authors.lastname: Kalynchuk
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000378:metabolism / Q000503:physiopathology*; D002421:Caudate Nucleus / Q000378:metabolism / Q000503:physiopathology*; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007696:Kindling, Neurologic; D008297:Male; D011939:Mental Recall / Q000502:physiology; D009473:Neuronal Plasticity; D009478:Neuropeptide Y / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*
chemical_list: D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor
keywords: Amygdala; Caudate nucleus; Fear conditioning; Hippocampus; Kindling; NPY; c-fos