The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.
We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.
Viral vectors are excellent tools for studying gene function in the brain, although a limitation has been the ability to effectively target transgene expression to specific neuronal populations. This generally cannot be overcome by the use of neuron-specific promoters, as most are too large to be used with current viral vectors and expression from these promoters is often relatively weak. We therefore developed a composite expression cassette, comprising 495 bp of the weak human SYN1 (synapsin-1) promoter and 800 bp of the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). Studies in hippocampal cultures, organotypic cultures, and in vivo showed that the 3' addition of the WPRE to the SYN1 element greatly increased enhanced green fluorescent protein expression levels with no loss of neuronal specificity. In vivo studies also showed that transgene expression was enhanced with no loss of neuronal specificity in dentate-gyrus neurons for at least 6 weeks following transfection. Therefore, unlike most powerful promoter systems, which mediate expression in neurons and glia, this SYN1-WPRE cassette can target powerful long-term transgene expression to central nervous system neurons when delivered at relatively low titers of adenovirus. Its use should therefore facilitate both gene therapy studies and investigations of neuronal gene function.
Multiple sclerosis is a currently incurable inflammatory demyelinating syndrome. Recent reports suggest that bone marrow derived mesenchymal stem cells may have therapeutic potential in experimental models of demyelinating disease, but various alternative mechanisms, ranging from systemic immune effects to local cell replacement, have been proposed. Here we used intraperitoneal delivery of human mesenchymal stem cells to help test (a) whether human cells can indeed suppress disease, and (b) whether CNS infiltration is required for any beneficial effect. We found pronounced amelioration of clinical disease but profoundly little CNS infiltration. Our findings therefore help confirm the therapeutic potential of mesenchymal stem cells, show that this does indeed extend to human cells, and are consistent with a peripheral or systemic immune effect of human MSCs in this model. Keywords Mesenchymal stem cells; Multiple sclerosis; Experimental allergic encephalomyelitisMultiple sclerosis is an acquired inflammatory demyelinating syndrome of unknown cause, and which is currently incurable. In many individuals, progressive disability occurs during the course of the disease, as a consequence of irreversible CNS damage. The ineffectiveness of current therapies has emphasised the importance of novel treatment approaches, and stem cells are widely held as having particular promise.Bone marrow derived mesenchymal stem cells can proliferate substantially, and can differentiate into cells of all three germ cell layers, including neural cells; moreover they are relatively accessible, could be used for autologous therapy, and are capable of entering the CNS (particularly when damaged) from the circulation [6,11]. They are therefore considered good candidates for early clinical stem cell therapeutic studies.Recently, reports have appeared suggesting that bone marrow-derived cells can ameliorate toxic and inflammatory experimental demyelinating disease following intravenous delivery [1,3,5,7,[13][14][15][16]. However, whether this effect is achieved through cell replacement and
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