title: Deconstructing the neural and ionic involvement of seizure-like events in the striatal network.
abstract: Seizures occur in the basal ganglia (BG) of epileptic patients and in animal models of epilepsy, but there is relatively little known about how these events are gated and/or propagated through this structure. Here, we present and characterize a model of in vitro seizure-like events (SLEs) in the striatum by applying chemostimulants to brain slices from young rat pups. We found that bath perfusion of artificial cerebral spinal fluid (aCSF) containing 0.25 mM MgCl(2), 5mM KCl and 100 μM 4-aminopyridine (LM/HK/4AP) elicited recurrent hyper-excitability in striatal medium spiny neurons (MSNs) in the form of paroxysmal depolarization shifts (PDSs) with an amplitude of 27.8 ± 2.1 mV and a duration of 29.4 ± 3.7s. PDSs coincided with SLEs in the striatal network with an amplitude of 106.5 ± 11.3 μV, duration of 23.6 ± 3.2 s, and a spiking frequency of 7.9 ± 1.3 Hz. Notably, chemostimulant-induced MSN PDSs were predominantly observed at earlier ages (P7-11), whereas occurrence of MSN PDSs declined to 50% by P12 and were no longer noted after P14; antagonism of the cannabinoid receptor (CB1) with 10 μM LY 320135 along with perfusion of LM/HK/4AP in older animals (P14-15) was unable to elicit MSN PDSs and SLEs. PDSs and SLEs were blocked with 60 μM 2-amino-5-phosphonopentanoate (APV), an N-methyl-d-aspartate receptor (NMDAR) blocker, or with traditional anticonvulsants such as 100 μM phenytoin or 50 μM carbamazepine. Conversely, blockade of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptors (AMPARs) with 10 μM CNQX or T- and L-type Ca(2+) channels with 50 μM NiCl(2) or 50 μM nimodipine, respectively, did not significantly change MSN PDS and SLE amplitudes, durations and frequencies seen with LM/HK/4AP treatment alone. Striatal SLEs were driven by MSN hyper-excitability and synchrony since neither the presence of 1μM scopolamine, a muscarinic acetylcholine (ACh) receptor inhibitor, nor selective inhibition of fast-spiking interneurons (FSIs) with 50μM IEM1460 had any significant effect on MSN PDSs and SLEs. Next, we physically isolated the striatum from cortical and thalamic input and found that the striatum was intrinsically capable of manifesting NMDAR-dependent SLEs. Altogether, the present study is the first to deconstruct how SLEs can form in the striatum by examining how MSN activity coincides with SLEs. It also highlights a previously unrecognized potential for the striatum to manifest SLEs in vitro, without involving the cortex and thalamus. From these findings, further hypotheses can be developed for studying the BG's role in seizure generation and propagation, which may lead to novel pharmacological targets for the treatment of epilepsy.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Yu
authors.forename: Megan
authors.initials: M
authors.lastname: Calos
authors.forename: Julie
authors.initials: J
authors.lastname: Pilitsis
authors.forename: Damian Seung-Ho
authors.initials: DS
authors.lastname: Shin
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D012640:Seizures / Q000503:physiopathology*
chemical_list: D000927:Anticonvulsants; D001572:Benzofurans; D063387:Cannabinoid Receptor Antagonists; D043884:Receptor, Cannabinoid, CB1; D002220:Carbamazepine; D010672:Phenytoin; C110158:LY 320135