HT2CRMediated Contributions to Cognitive Behaviors

Behaviors traditionally associated with cognitive function, including different aspects of long and short-term memory, behavioral planning, and behavioral inhibition are organized across a broad extent of the neuraxis and encompass regions of the cortex, basal ganglia, hippocampus, amygdala, and extended amygdala. 5-HT2CR expression has been demonstrated in all of these regions (Eberle-Wang et al. 1997; Filip and Cunningham 2002; Huang et al. 2004; Krishnakumar et al. 2009; Pompeiano et al. 1994; Serrats et al. 2005). Thus, 5-HT2CRs may potentially regulate a large number of cognitive behaviors.

How 5-HT2CRs modulate hippocampal function is currently best understood. Prior studies have demonstrated that constitutive 5-HT2CR /Y mutant mice possess a specific deficit in long term potentiation at the first major synaptic integration point of the hippocampus, the medial perforant pathway synapse onto dentate gyrus pyramidal cells (Tecott et al. 1998). This LTP deficit is not present in any of the other downstream hippocampal synaptic circuits, including the dentate to CA3 synapse, the CA3 to CA1 synapse, or the CA1 to subiculum synapse. 5-HT2CR mutant mice have normal hippocampal cytoarchitecture when assessed by light microscopy of stained tissue, and demonstrate no significant differences in either hippocampal 5-HT2AR expression or overall hippocampal catecholamine content compared with wild-type mice.

This specific deficit in hippocampal LTP had a testable behavioral correlate in the Morris water maze assay of spatial memory. While both wild type and constitutive

5-HT2CR -/Y mice demonstrated similar performances in learning trials to find the location of the submerged platform, constitutive 5-HT2CR /Y mutant mice did not focus their search within the trained quadrant on performance of the "probe" trial. This deficit in place memory is often observed in animals with deficits in information processing at the perforant path to dentate gyrus synapse (Xavier and Costa 2009). Of note, no genotypic differences in "freezing" behavior evoked by exposure to an environment where the mice had previously received a mild aversive stimulus were observed. Thus, loss of 5-HT2CR function leads to a very selective deficit in hippocampal learning.

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