title: Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices.
abstract: In human disease, channelopathies involving functional reduction of the delayed rectifier potassium channel α-subunit Kv1.1 - either by mutation or autoimmune inhibition - result in temporal lobe epilepsy. Kv1.1 is prominently expressed in the axons of the hippocampal tri-synaptic pathway, suggesting its absence will result in widespread effects on normal network oscillatory activity. Here, we performed in vitro extracellular recordings using a multielectrode array to determine the effects of loss of Kv1.1 on spontaneous sharp waves (SPWs) and high frequency oscillations (HFOs). We found that Kcna1-null hippocampi generate SPWs and ripples (80-200Hz bandwidth) with a 50% increased rate of incidence and 50% longer duration, and that epilepsy-associated pathologic HFOs in the fast ripple bandwidth (200-600Hz) are also present. Furthermore, Kcna1-null CA3 has enhanced coupling of excitatory inputs and population spike generation and CA3 principal cells have reduced spike timing reliability. Removing the influence of mossy fiber and perforant path inputs by micro-dissecting the Kcna1-null CA3 region mostly rescued the oscillatory behavior and improved spike timing. We found that Kcna1-null mossy fibers and medial perforant path axons are hyperexcitable and produce greater pre- and post-synaptic responses with reduced paired-pulse ratios suggesting increased neurotransmitter release at these terminals. These findings were recapitulated in wild-type slices exposed to the Kv1.1 inhibitor dendrotoxin-κ. Collectively, these data indicate that loss of Kv1.1 enhances synaptic release in the CA3 region, which reduces spike timing precision of individual neurons leading to disorganization of network oscillatory activity and promotes the emergence of fast ripples.
authors: Creighton University, Department of Pharmacology, Omaha, NE 68174, USA. timothysimeone@creighton.edu
authors: Timothy A
authors: TA
authors: Simeone
authors: Kristina A
authors: KA
authors: Simeone
authors: Kaeli K
authors: KK
authors: Samson
authors: Do Young
authors: DY
authors: Kim
authors: Jong M
authors: JM
authors: Rho
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000502:physiology*; D005071:Evoked Potentials / Q000502:physiology*; D051662:Kv1.1 Potassium Channel / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D009924:Organ Culture Techniques
chemical_list: D051662:Kv1.1 Potassium Channel