ABSTRACT
OBJECTIVE: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory. METHODS: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory. RESULTS: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult. SIGNIFICANCE: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.
Subject(s)
Cognitive Dysfunction/physiopathology , Epilepsy, Temporal Lobe/physiopathology , Interneurons , Optogenetics/methods , Spatial Learning , Spatial Memory , Animals , Channelrhodopsins , Chronic Disease , Cognitive Dysfunction/psychology , Cognitive Dysfunction/therapy , Disease Models, Animal , Electroencephalography , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/psychology , Epilepsy, Temporal Lobe/therapy , Excitatory Amino Acid Agonists/toxicity , Hippocampus , Kainic Acid/toxicity , Mice , Parvalbumins , Video RecordingABSTRACT
Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.
Subject(s)
Epilepsy, Temporal Lobe/physiopathology , Mossy Fibers, Hippocampal/physiology , Mossy Fibers, Hippocampal/physiopathology , Seizures/physiopathology , Spatial Memory/physiology , Animals , Disease Models, Animal , Electroencephalography , Female , Male , Mice , Mice, Inbred C57BL , Neurons/physiology , OptogeneticsABSTRACT
The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.
Subject(s)
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Receptor, Cannabinoid, CB1/metabolism , Spatial Memory/physiology , Synaptic Potentials/genetics , Animals , Benzoxazines/pharmacology , Biophysical Phenomena/drug effects , Biophysical Phenomena/genetics , Calcium Channel Blockers/pharmacology , Cyclic GMP/metabolism , Dendrites/physiology , Enzyme Inhibitors/pharmacology , Hippocampus/cytology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase 4/metabolism , Membrane Potentials/drug effects , Membrane Potentials/genetics , Mice , Mice, Transgenic , Morpholines/pharmacology , Mutation/genetics , Naphthalenes/pharmacology , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Nitric Oxide Synthase/metabolism , Receptor, Cannabinoid, CB1/genetics , Signal Transduction/genetics , Signal Transduction/radiation effects , Spatial Memory/drug effects , Synaptic Potentials/drug effectsABSTRACT
Epilepsy is a complex disorder involving neurological alterations that lead to the pathological development of spontaneous, recurrent seizures. For decades, seizures were thought to be largely repetitive, and had been examined at the macrocircuit level using electrophysiological recordings. However, research mapping the dynamics of large neuronal populations has revealed that seizures are not simply recurrent bursts of hypersynchrony. Instead, it is becoming clear that seizures involve a complex interplay of different neurons and circuits. Herein, we will review studies examining microcircuit changes that may underlie network hyperexcitability, discussing observations from network theory, computational modeling, and optogenetics. We will delve into the idea of hub cells as pathological centers for seizure activity, and will explore optogenetics as a novel avenue to target and treat pathological circuits. Finally, we will conclude with a discussion on future directions in the field.
Subject(s)
Epilepsy/physiopathology , Neural Pathways/physiopathology , Brain/physiopathology , Dentate Gyrus/physiopathology , Epilepsy/etiology , Humans , Neural Networks, Computer , Neurons/physiology , OptogeneticsABSTRACT
Molecular changes that underlie evolutionary changes in behavior and physiology are not well understood. Dauer formation in Caenorhabditis elegans is a temperature-sensitive process controlled through a network of signaling pathways associated with sensory neurons and is potentially an excellent system in which to investigate molecular changes in neuronal function during evolution. To begin to investigate the evolution of dauer formation in the genus Caenorhabditis at the molecular level, we isolated dauer-formation mutations in C. briggsae, a species closely related to the model organism C. elegans. We identified mutations in orthologs of C. elegans genes daf-2 (insulin receptor), daf-3 (Smad), and daf-4 (TGF-beta type 2 receptor), as well as genes required for formation of sensory cilia. Phenotypic analyses revealed that functions of these genes are conserved between C. elegans and C. briggsae. Analysis of C. briggsae mutations also revealed a significant difference between the two species in their responses to high temperatures (>26 degrees). C. elegans is strongly induced to form dauers at temperatures above 26 degrees, near the upper limit for growth of C. elegans. In contrast, C. briggsae, which is capable of growth at higher temperatures than C. elegans, lacks this response.
