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Clozapine-N-Oxide (CNO) impairs hippocampus-dependent memory formation, while Compound 21 (C21) does not. This suggests C21 is a better choice for chemogenetic studies on memory and hippocampal function.

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Area of Science:

  • Neuroscience
  • Cognitive Science
  • Pharmacology

Background:

  • Chemogenetics, using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), allows precise neuronal manipulation.
  • Clozapine-N-Oxide (CNO) was thought inert but metabolizes to clozapine, causing off-target effects.
  • Compound 21 (C21) offers improved selectivity over CNO.

Purpose of the Study:

  • To compare the acute effects of CNO and C21 on hippocampus-dependent memory formation.
  • To investigate the impact of CNO and C21 on hippocampal neuronal and interneuron activity during memory encoding.

Main Methods:

  • Object-location memory (OLM) paradigm in mice to assess spatial memory encoding.
  • Measurement of cFos expression in hippocampal principal neurons and parvalbumin (PV+) interneurons.

Main Results:

  • Neither CNO nor C21 altered overall hippocampal neuronal or PV+ interneuron activity during memory encoding.
  • CNO administration significantly impaired OLM encoding performance.
  • C21 administration did not affect OLM encoding performance.

Conclusions:

  • CNO exerts an unappreciated behavioral effect on hippocampus-dependent memory, independent of DREADD expression.
  • C21 demonstrates superior specificity and may be a more suitable ligand for memory and hippocampal chemogenetic research.