Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation.

Exposure to stress causes dysfunctions in circuits connecting hippocampus and prefrontal cortex (H-PFC). Long term potentiation (LTP) induced in vivo in rats at H-PFC synapses is impaired by acute elevated platform stress in a manner that can be restored by treatment with certain antidepressants. To identify biochemical pathways in rat frontal cortex underlying this stress-mediated impairment of synaptic plasticity, we examined the phosphorylation state of receptors, signaling proteins and transcription factors implicated in neuronal plasticity. Transient changes in the phosphorylation states of Ser217/221-MEK, Thr183/Tyr185-p42MAPK, Thr202/Tyr204-p44MAPK, Thr180/Tyr182-p38MAPK, Thr218/Tyr220-ERK5, Thr308-Akt, Ser63-ATF-1, Ser1303-GluN2B, Tyr490/515-TrkA/B were found. BDNF was down-regulated after elevated platform stress suggesting that it could regulate the MEK/MAPK signaling cascade. Acute treatment with the antidepressants tianeptine and imipramine reversed the stress-induced down-regulation of P-Ser217/221-MEK. However, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1. Altogether, these results indicate that acute elevated platform stress down-regulates a putative BDNF/MEK/MAPK signaling cascade in the frontal cortex in a manner that is reversible by the antidepressants tianeptine and imipramine. Moreover, changes in LTP may be associated with phosphorylation of AMPA receptors and with some specificity for certain antidepressants. Indeed, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1, indicating a potential effect on AMPA receptor phosphorylation being involved in the reversal of LTP.

Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling.

We previously reported that exposure to acute and chronic stress impairs long-term potentiation (LTP) in the hippocampal-prefrontal cortex pathway and showed evidence for a fundamental role of the prefrontal cortex in maladaptive responses to stress. The goal of the current studies was to examine whether blockade of glucocorticosteroid receptors (GR), by mifepristone (a Type II glucocorticoid receptor antagonist), just after exposure to acute stress could prevent stress-induced impairment of prefrontal LTP. We further examine the effects of mifepristone on mitogen-activated protein/ERK kinase (MEK) signaling pathway in the prefrontal cortex. The data show that an acute injection of mifepristone after stress restored the stress-induced blockade of prefrontal LTP and reduction of phospho-Ser217/221-MEK. These findings have significance for the treatment of memory deficits in hypercortisolemic states, such as stress and depression.

Common efficacy of psychotropic drugs in restoring stress-induced impairment of prefrontal plasticity.

We recently investigated the effects of stress on synaptic plasticity in the prefrontal cortex, namely the prelimbic area or the apparent homologue of the primate subgenual prefrontal cortex in humans where most of the hippocampal terminal fields are localized. Exposure to an acute stress causes a remarkable and long-lasting inhibition of long term potentiation (LTP) in the frontal cortex evoked by stimulation of hippocampal outflow and this impairment is prevented by the glucocorticoid receptor antagonist mifepristone. Thus, the frontal cortex is also a target for glucocorticoids involved in the stress response. Current data show that antidepressants of various types, i.e., tianeptine and fluoxetine, at doses normally used in antidepressant testing, restore LTP impaired by prior acute stress. Interestingly, clozapine administered in a similar way after stress rapidly reverses the stress-induced impairment of LTP at doses which do not affect LTP alone. This stress paradigm highlights comorbidity for both etiology and treatment of psychiatric disorders like depression and schizophrenia. Restoring appropriate cognitive functions in circuits associated with dysfunctions in coping with stress may be proposed as a new systems-level approach to drug discovery and development. We are presently investigating the involvement of signalling molecules in producing these plastic changes.

Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: importance for psychiatric diseases.

The direct hippocampal to prefrontal cortex pathway and its changes in synaptic plasticity is a useful framework for investigating the functional operations of hippocampal-prefrontal cortex communication in cognitive functions. Synapses on this pathway are modifiable and synaptic strength can be turned up or down depending on specific patterns of activity in the pathway. The objective of this review will be to summarize the different studies carried out on this topic including very recent data and to underline the importance of animal models for the development of new and effective medications in psychiatric diseases. We have shown that long-term potentiation (LTP) of hippocampal-prefrontal synapses is driven by the level of mesocortical dopaminergic (DA) activity and more recently that stress is also an environmental determinant of LTP at these cortical synapses. Stimulation of the ventral tegmental area at a frequency known to evoke DA overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of hippocampal-prefrontal cortex LTP whereas a depletion of cortical DA levels generates a dramatic decrease in this LTP. Moreover, hippocampal stimulation induces a transient but significant increase in DA release in the prefrontal cortex and an optimal level of D1 receptor activation is essential for LTP expression. We recently investigated the impact of stress on hippocampal-prefrontal LTP and demonstrated that exposure to an acute stress causes a remarkable and long-lasting inhibition of LTP. Furthermore, we demonstrated that tianeptine, an antidepressant which has a unique mode of action, and clozapine an atypical antipsychotic when administered at doses normally used in human testing are able to reverse the impairment in LTP. Stressful life events have a substantial causal association with psychiatric disorders like schizophrenia and depression and recent imaging studies have shown an important role of the limbic-cortical circuit in the pathophysiology of these illnesses. Therefore, we proposed that agents capable of reversing the impairment of plasticity at hippocampal to prefrontal cortex synapses have the potential of becoming new therapeutic classes of antidepressant or antipsychotic drugs.

Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants.

Acute stress inhibits long-term potentiation (LTP) at synapses from the hippocampus to prefrontal cortex in the rat, a model of the dysfunction in the anterior cingulate/orbitofrontal cortices which has been observed in human depression. We demonstrate that the antidepressants tianeptine and, to a lesser extent, fluoxetine, are able to reverse the impairment in LTP, a measure of frontal synaptic plasticity, caused by stress on an elevated platform. LTP was induced by stimulation of hippocampal outflow. Beneficial effects on neuronal plasticity, defined as a reversal of the effects of stress in this paradigm, can be considered as a new animal model for the impact of stress on hippocampal/frontal circuits, a key target in psychiatric diseases.