Prenatal exposure to ketamine in rats: Implications on animal models of schizophrenia.

Schizophrenia is a complex neuropsychiatric disorder characterized by hallucinations, delusions, anhedonia, flat affect and cognitive impairments. The aim of this study was to propose a prenatal treatment with ketamine, a psychedelic drug that acts as a non-competitive inhibitor of glutamate NMDA receptors, as a neurodevelopmental animal model of schizophrenia. The drug was applied (i.m. 60 mg.kg-1 h-1 ) in pregnant Sprague-Dawley rats on gestational Day 14. Offspring behavior was studied on pubertal (4 weeks old) and adult (10 weeks old) stages. Also, hippocampal CA1-CA3 morphology was assessed in adult animals through a Nissl stain. Results showed a disinhibition and hyperactive behavior in pubertal animals exposed to ketamine, followed in adulthood with cognitive impairments, social withdrawal, anxiety, depression, and aggressive-like behaviors. In the hippocampus, a reduction of the CA3 layer thickness was observed, without changes in cell density. These results strongly suggest a robust link between prenatal pharmacologic manipulation of NMDA receptors and schizophrenia.

Involvement of hippocampal inputs and intrinsic circuit in the acquisition of context and cues during classical conditioning in behaving rabbits.

Learning-related changes in strength in selected hippocampal synapses have been described recently. However, information is scarce regarding the spatial-temporal sequence of changes in synaptic weights taking place during the acquisition of a classical conditioning task and the contribution of both context (environmental details) and cues (conditioned and unconditioned stimuli: CS, US) to those activity-dependent changes. We recorded in rabbits the monosynaptic field excitatory postsynaptic potentials (fEPSPs) evoked at 6 different hippocampal synapses during the acquisition and extinction of a classical eyeblink conditioning using trace or delay paradigms, as well as during pseudoconditioning and in the absence of CS and US presentations (context). Context and pseudoconditioning training evoked early, lasting changes in synaptic strength in perforant pathway synapses in dentate gyrus (PP-DG), and hippocampal CA3 (PP-CA3) and CA1 (PP-CA1) areas. Pseudoconditioning also evoked early, nonlasting changes in strength within the intrinsic hippocampal circuit (CA3-CA1 and CA3-cCA1 synapses). In contrast, during both trace and delay training sessions, synaptic changes in strength were mostly noticed within the intrinsic hippocampal circuit (DG-CA3, CA3-CA1, CA3-cCA1). The response of hippocampal synapses to afferent impulses seems to be modulated by both context and cues during associative learning in behaving rabbits.

Red nucleus neurons actively contribute to the acquisition of classically conditioned eyelid responses in rabbits.

The red nucleus (RN) is a midbrain premotor center that has been suggested as being involved in the acquisition and/or performance of classically conditioned nictitating membrane/eyelid responses. We recorded in rabbits the activity of RN and pararubral neurons during classical eyeblink conditioning using a delay paradigm. Neurons were identified by their antidromic activation from contralateral facial and accessory abducens nuclei and by their synaptic activation from the ipsilateral motor cortex (MC) and the contralateral cerebellar interpositus (IP) nucleus. For conditioning, we used a tone as a conditioned stimulus (CS) followed 250 ms later by a 100 ms air puff as an unconditioned stimulus (US) coterminating with it. Conditioned responses (CRs) were determined from the evoked changes in the electromyographic activity of the orbicularis oculi (OO) muscle. Recorded neurons were classified by their antidromic activation and by their changes in firing rate during the CS-US interval. Identified neurons increased their firing rates in relation to the successive conditioning sessions, but their discharge rates were related more to the EMG activity of the OO muscle than to the learning curves. Reversible inactivation of the IP nucleus with lidocaine during conditioning evoked a complete disappearance of both conditioned and unconditioned eyelid responses, and a progressive decrease in CR-related activity of RN neurons. In contrast, MC inactivation evoked a decrease in the acquisition process and an initial disfacilitation of neuronal firing (which was later recovered), together with the late appearance of CRs. Thus, RN neurons presented learning-dependent changes in activity following MC inactivation.