The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research.

In temporal lobe epilepsy, changes in synaptic and intrinsic properties occur on a background of altered network architecture resulting from cell loss and axonal sprouting. Although modeling studies using idealized networks indicated the general importance of network topology in epilepsy, it is unknown whether structural changes that actually take place during epileptogenesis result in hyperexcitability. To answer this question, we built a 1:1 scale structural model of the rat dentate gyrus from published in vivo and in vitro cell type-specific connectivity data. This virtual dentate gyrus in control condition displayed globally and locally well connected ("small world") architecture. The average number of synapses between any two neurons in this network of over one million cells was less than three, similar to that measured for the orders of magnitude smaller C. elegans nervous system. To study how network architecture changes during epileptogenesis, long-distance projecting hilar cells were gradually removed in the structural model, causing massive reductions in the number of total connections. However, as long as even a few hilar cells survived, global connectivity in the network was effectively maintained and, as a result of the spatially restricted sprouting of granule cell axons, local connectivity increased. Simulations of activity in a functional dentate network model, consisting of over 50,000 multicompartmental single-cell models of major glutamatergic and GABAergic cell types, revealed that the survival of even a small fraction of hilar cells was enough to sustain networkwide hyperexcitability. These data indicate new roles for fractionally surviving long-distance projecting hilar cells observed in specimens from epilepsy patients.

In organotypic hippocampal slice cultures, principal neurons form aberrant excitatory connections with other principal cells in response to slicing-induced deafferentation, similar to mechanisms underlying epileptogenesis in post-traumatic epilepsy. To investigate the consequences of this synaptogenesis, we recorded field potential activity from area CA3 during perfusion with the complete growth medium used during incubation. At 7 days in vitro (DIV), slice cultures only displayed multi-unit activity. At 14 DIV the majority displayed population bursts reminiscent of interictal-like spikes, but sustained synchronous activity was rare. Bandpass filtering of interictal discharges revealed fast ripple-like complexes, similar to in vivo recordings. Spontaneous ictal-like activity became progressively more prevalent with age: at 21 DIV 50% of organotypic hippocampal slice cultures displayed long lasting, ictal-like discharges that could be suppressed by phenytoin, whereas interictal-activity was not suppressed. The fraction of cultures displaying ictal events continually increased with incubation time. Quantification of population spike activity throughout epileptogenesis using automatic detection and clustering algorithms confirmed the appearance of interictal-like activity before ictal-like discharges, and also revealed high frequency pathological multi-unit activity in slice cultures at 14–17 DIV. These experiments indicate that interictal-like spikes precede the appearance of ictal-like activity in a reduced in vitro preparation. Epileptiform activity in cultures resembled in vivo epilepsy, including sensitivity to anticonvulsants and steadily increasing seizure incidence over time, although seizure frequency and rate of epileptogenesis were higher in vitro. Organotypic hippocampal slice cultures comprise a useful model system for investigating mechanisms of epileptogenesis as well as developing anti-epileptic and anti-epileptogenic drugs.

HT 3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT 3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT 3 receptor antagonists in neurology-and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.