RT Journal Article
SR Electronic
T1 Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaai8753
DO 10.1126/scitranslmed.aai8753
VO 9
IS 421
A1 Riga, Danai
A1 Kramvis, Ioannis
A1 Koskinen, Maija K.
A1 van Bokhoven, Pieter
A1 van der Harst, Johanneke E.
A1 Heistek, Tim S.
A1 Jaap Timmerman, A.
A1 van Nierop, Pim
A1 van der Schors, Roel C.
A1 Pieneman, Anton W.
A1 de Weger, Anouk
A1 van Mourik, Yvar
A1 Schoffelmeer, Anton N. M.
A1 Mansvelder, Huib D.
A1 Meredith, Rhiannon M.
A1 Hoogendijk, Witte J. G.
A1 Smit, August B.
A1 Spijker, Sabine
YR 2017
UL http://stm.sciencemag.org/content/9/421/eaai8753.abstract
AB A common feature of major depression is cognitive impairment, including difficulties in memory recall. The underlying mechanisms of these symptoms are unclear. In a new study, Riga and colleagues used social defeat–induced persistent stress to induce a depressive-like state in rats and then examined molecular changes in the hippocampus related to cognitive deficits associated with this state. They found increased expression of extracellular matrix proteins and decreased plasticity potential and inhibitory neurotransmission in the dorsal hippocampus in this rat model. Treatment with an antidepressant drug or a single injection into the hippocampus of an enzyme that breaks down the extracellular matrix resulted in improved hippocampal function and rescue of memory recall in this preclinical rat model.Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat–induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.