Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotorstimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs.

The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel ␣ subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC 50 ϭ 25 M) and diclofenac (EC 50 ϭ 2.6 M) resulted in the activation of KCNQ2/Q3 K ϩ currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (Ϫ23 and Ϫ15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel ␣ subunits. In contrast, they did not enhance KCNQ1 K ϩ currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED 50 ϭ 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.Voltage-dependent K ϩ (Kv) channels play a major role in brain excitability through the regulation of action potential generation and propagation, the tuning of neuronal firing patterns, or the modulation of neurotransmitter release. The M-type K ϩ channel generates a subthreshold, voltage-gated K ϩ current (M-current) that plays an important role in controlling neuronal excitability. Brown and Adams (1980) first identified the M-current in frog sympathetic neurons as a slowly activating, noninactivating, voltage-sensitive K ϩ current, which was inhibited by muscarinic acetylcholine receptor stimulation (Brown and Adams, 1980). M-currents were also characterized in hippocampal and cortical neurons (Brown, 1988;Marrion, 1997;Cooper and Jan, 2003). Modulation of the M-current has profound effects on brain excitability because this noninactivating K ϩ channel exhibits significant conductance in the voltage range of action potential initiation. The low-threshold gating and the slow activation and deactivation of the M-current act as a brake for repetitive firing and neuronal excitability (

A sulfated, myotropic neuropeptide termed leucosulfakinin (Glu-Gln-Phe-Glu-Asp-Tyr(SO3H)-Gly-His-Met-Arg-Phe-NH2) was isolated from head extracts of the cockroach Leucophaea maderae. The peptide exhibits sequence homology with the hormonally active portion of the vertebrate hormones human gastrin II and cholecystokinin, suggesting that these peptides are evolutionarily related. Six of the 11 amino acid residues (55 percent) are identical to those in gastrin II. In addition, the intestinal myotropic action of leucosulfakinin is analogous to that of gastrin.

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The M-type K ϩ current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K ϩ channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre-and postsynaptic M-channels using a novel Kv7.2/3 channel opener, NH6, which we synthesized as a new derivative of N-phenylanthranilic acid. NH6 exhibits a good selectivity as it does not affect Kv7.1 and I KS K ϩ currents as well as NR1/NR2B, AMPA, and GABA A receptor-mediated currents. Superfusion of NH6 increased recombinant Kv7.2/3 current amplitude (EC 50 ϭ 18 M) by causing a hyperpolarizing shift of the voltage activation curve and by markedly slowing the deactivation kinetics. Activation of native M-currents by NH6 robustly reduced the number of evoked and spontaneous action potentials in cultured cortical, hippocampal and dorsal root ganglion neurons. In hippocampal slices, NH6 decreased somatically evoked spike afterdepolarization of CA1 pyramidal neurons and induced regular firing in bursting neurons. Activation of M-channels by NH6, potently reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) postsynaptic currents without affecting their amplitude and waveform, thus suggesting that Mchannels presynaptically inhibit glutamate and GABA release. Our results suggest a role of presynaptic M-channels in the release of glutamate and GABA. They also indicate that M-channels act pre-and postsynaptically to dampen neuronal excitability.

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