Neuron Navigator 1Regulates Learning, Memory, and the Response to Multiple Potentially Addictive Drugs

AbstractGenetic variation accounts for much of the risk for developing a substance use disorder (SUD). Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine intravenous self-administration (IVSA). Computational genetic analysis of IVSA data obtained from an inbred strain panel identifiedNav1,a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this hypothesis, we generated and characterizedNav1knockout (KO) mice.Nav1KO mice exhibited increased cocaine intake during IVSA testing. Surprisingly,Nav1KO mice also displayed a reduced susceptibility to become opioid dependent or develop opioid-induced hyperalgesia after chronic morphine administration, and had impaired spatial learning/memory. Immunohistochemistry and electrophysiology studies revealed that inhibitory synapse density in the cortex ofNav1KO mice was reduced, and excitatory synaptic transmission was increased in theNav1KO cortex and hippocampus. Transcriptomic analysis revealed thatNav1KO mice had a marked increase in excitatory neurons in a deep cortical layer. Collectively, our results indicate thatNav1regulates learning, memory, and the response to multiple addictive drugs, and that changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus could possibly mediate these phenotypic effects.