Past events

Abstract: Past neurobiological models of mood disorders have not considered etiology or a developmental perspective. Recently enough data regarding candidate genes and the impact of adverse early experience has been published that the beginnings of a plausible and heuristically useful hypothetical causal model can be proposed. This talk will integrate known effects of susceptibility genes and childhood adversity in explaining the psychopathology and biological phenotype of major depression including data from postmortem studies and in vivo brain imaging.

The last twenty years of intense research have provided convincing evidence for a role of regulation of gene expression in control of long-term neuronal plasticity, including learning and memory. Starting from our discovery–in late eighties–of c-fos activation in those phenomena, we have focused on correlating the expression of c-fos mRNA and c-Fos protein in various cognition-related brain structures with neuronal plasticity, learning and memory. The major conclusion from our studies, as well as those by the others, is that c-Fos and its functional form, AP-1 transcription factor, is the best correlate of learning processes, especially of a novelty of the behavioral information, whose processing constitutes the very foundation of the learning phenomenon. However, our understanding of exact biological function(s) of c-Fos/AP-1 still remains largely missing. Recently, an extracellular proteolytic system, composed of tissue inhibitor of matrix metalloproteinases, TIMP-1 and matrix metalloproteinase-9, MMP-9, has emerged as a major AP-1 target in hippocampal neurons responding to enhanced neuronal activity. Structural remodeling of the dendritic spines and synapses is essential for synaptic plasticity, underlying learning and memory. Matrix metalloproteinases are pivotal for tissue remodeling throughout the body, especially during development. Matrix metalloproteinase 9 (MMP-9) is an extracellularly operating enzyme that have recently been implicated in dendritic remodeling, synaptic plasticity, learning and memory (Szklarczyk et al., J. Neurosci., 2002; Nagy et al., J. Neurosci., 2006; Okulski et al., Biol. Psych., 2007). Furthermore, we have recently identified MMP-9 as a being produced, expressed and active at the synaptic contacts (Konopacki et al., Neuroscience, 2007; Michaluk et al., J. Biol. Chem., 2007; Wilczynski et al., J. Cell Biol. in press). Most recently, we have also found that MMP-9 plays a key pathogenic role in two animal models of temporal lobe epilepsy (TLE): kainate-evoked-epilepsy and pentylenetetrazole (PTZ) kindling-induced epilepsy. TLE is a devastating disease in which aberrant synaptic plasticity plays a major role Notably, we show that the sensitivity to PTZ-epileptogenesis is decreased in MMP-9 KO mice, but is increased in novel strain of transgenic rats, we have produced to overexpress MMP-9 selectively in neurons. Immunoelectron microscopy has revealed that MMP-9 associates with hippocampal dendritic spines bearing asymmetric (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9-deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis following mossy-fibers sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.

Sensory perception in natural environments involves the dual challenge to encode external stimuli and manage the influence of changes in body position that alter the sensory field. To examine mechanisms used to integrate sensory signals elicited by both external stimuli and motor activity, we use a mixture of psychophysics and electrophysiology to study rats trained to perform an active sensory task with a single vibrissa. We identify a nonlinear interaction between vibrissa touch and a motion-derived signal that dynamically labels each neuron with a preferred phase. The observed response enables the rodent to estimate object position in a head-centered reference frame. More generally, our result delineates a computation that is likely to occur in all active sensorimotor systems.