Ketamine modulates the action of serotonin on prelimbic and infralimbic areas of the prefrontal cortex. An in vivo study

Trabajo presentado en Barcelona Computational, Cognitive and Systems Neuroscience (BARCCSYN), celebrado del 16 al 17 de junio de 2016[Introduction] Major depressive disorder (MD) is a severe psychiatric disorder with a high prevalence. The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin (5-HT) and/or noradrenaline (NA) reuptake. These treatments require several weeks to induce a full clinical effect and many depressed patients show limited or no improvement. Clinical and preclinical studies have shown that ketamine, a non-competitive antagonist of the NMDA-R, at subanesthetic doses, induces immediate and long lasting effects in treatment-resistant depressed patients and antidepressant-like effects in animal models (1,2). The mechanisms underlying its therapeutic effects are not fully understood. In rodents, the infralimbic (IL) and prelimbic (PL) region of the medial prefrontal cortex (mPFC) are, respectively, the homologous areas of the human ventral anterior cingulate cortex and the dorsolateral PFC, key areas in the pathophysiology of MD. In the present study, we investigate the actions of ketamine on the activity of pyramidal and GABAergic neurons of the PL and IL area of the rat mPFC and also how ketamine modulates the responses in these neurons after physiological stimulation of the dorsal raphe nucleus (DR).[Methods] Neuronal discharge and local field potentials were recorded in the PL and IL of chloral hydrate anesthetized rats (n=10 controls, n=16 ketamine) using silicon probes (Neuronexus CM32; 4 tetrodes/area). GABAergic and pyramidal neurons were identified by action potential characteristics using a k-means clustering algorithm and by antidromic stimulation from the DR. Neuronal firing rate was recorded during 2 hours after intravenous injection of ketamine (0, 0.25 and 2.5mg/kg; in 0.9% NaCl solution). Responses in PL and IL neurons evoked by DR stimulation were analyzed by measuring the magnitude and duration of inhibitory and excitatory responses from peristimulus-time histograms (PSTH) (before, 5, 60 and 120 minutes after ketamine).[Results] ketamine injections induced an overall rapid and long-lasting (2 hours) increase in the activity of mPFC neurons (with varying individual responses), with a more robust response observed in the PL area. Currently we are identifying at least three types of cortical neurons (putative GABAergic interneurons, DR-projecting pyramidal neurons and putative pyramidal neurons). Soon, we will be able to evaluate the effect of ketamine on the firing rate of these specifics populations and see how ketamine modulates the responses of these neurons to DR stimulation. Moreover, we will analyze the intra-mPFC relationship among the different cell types using joint peristimulus time histograms and crosscorrelation functions.Peer Reviewe