German Title: Einfluss veränderter CKAMP44 Expression im Hippokampus auf räumliches Referenz- / Arbeitsgedächtnis

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Abstract

The newly discovered brain-specific transmembrane protein CKAMP44 was shown to influence AMPA receptor function in the mouse hippocampus where the protein is differentially expressed. The low mRNA expression in CA1-neurons versus the high expression in DGneurons gives reason to hypothesize that the different CKAMP44 levels influence memory processes assigned to these subfields. The DG has long been proposed to provide the cellular substrate for the process of spatial pattern separation, whereas CA1 is assumed to be the basis of temporal pattern separation. To investigate these hypotheses, two mouse models of altered CKAMP44 expression were analyzed. Theoretically, a global knockout of CKAMP44 should influence a region with high endogenous CKAMP44 expression (DG) more than a region with low expression (CA1). Vice versa, CKAMP44 overexpression should exert a stronger influence on a region with low (CA1) than on a region with high expression (DG). Thus, the CKAMP44-/- mice served as a model to study the involvement of CKAMP44 in the DG-based spatial pattern separation. CKAMP44-/- mice failed to show any impairment in hippocampus-dependent spatial reference- and spatial working-memory tests including spatial pattern separation. In the second model, virusmediated CKAMP44 overexpression was confined to the hippocampus. Compared to Controls, CKAMP44HCoex mice made a similar number of errors during both spatial reference- and spatial working-memory test on the eight-arm radial arm maze. But a newly designed analysis of the working memory errors on the eight-arm radial arm maze and the chance-level performance during rewarded alternation revealed an impairment in the ability to process or retrieve stimulusspecific, recency-dependent memory in CKAMP44HCoex mice. Thus, the CKAMP44HCoex model adds further proof to the implicated role for CA1 in temporal pattern separation, and also provides the hitherto only model of altered hippocampal memory funciton upon manipulation of an AMPA receptor auxiliary protein.

Translation of abstract (English)

The newly discovered brain-specific transmembrane protein CKAMP44 was shown to influence AMPA receptor function in the mouse hippocampus where the protein is differentially expressed. The low mRNA expression in CA1-neurons versus the high expression in DGneurons gives reason to hypothesize that the different CKAMP44 levels influence memory processes assigned to these subfields. The DG has long been proposed to provide the cellular substrate for the process of spatial pattern separation, whereas CA1 is assumed to be the basis of temporal pattern separation. To investigate these hypotheses, two mouse models of altered CKAMP44 expression were analyzed. Theoretically, a global knockout of CKAMP44 should influence a region with high endogenous CKAMP44 expression (DG) more than a region with low expression (CA1). Vice versa, CKAMP44 overexpression should exert a stronger influence on a region with low (CA1) than on a region with high expression (DG). Thus, the CKAMP44-/- mice served as a model to study the involvement of CKAMP44 in the DG-based spatial pattern separation. CKAMP44-/- mice failed to show any impairment in hippocampus-dependent spatial reference- and spatial working-memory tests including spatial pattern separation. In the second model, virusmediated CKAMP44 overexpression was confined to the hippocampus. Compared to Controls, CKAMP44HCoex mice made a similar number of errors during both spatial reference- and spatial working-memory test on the eight-arm radial arm maze. But a newly designed analysis of the working memory errors on the eight-arm radial arm maze and the chance-level performance during rewarded alternation revealed an impairment in the ability to process or retrieve stimulusspecific, recency-dependent memory in CKAMP44HCoex mice. Thus, the CKAMP44HCoex model adds further proof to the implicated role for CA1 in temporal pattern separation, and also provides the hitherto only model of altered hippocampal memory funciton upon manipulation of an AMPA receptor auxiliary protein.