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Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the postnatal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory. Here, we assessed the impact of neuronal expression of netrin-1 in the adult brain on behavior using tests of learning and memory. We show that adult mice exhibit impaired spatial memory following conditional deletion of netrin-1 from glutamatergic neurons in the hippocampus and neocortex. Further, we provide evidence that mice with conditional deletion of netrin-1 do not display aberrant anxiety-like phenotypes and show a reduction in self-grooming behavior. These findings reveal a critical role for netrin-1 expressed by neurons in the regulation of spatial memory formation.

Background and Purpose: Inward rectifier potassium (KIR) channels are key effectors of vasodilatation in neurovascular coupling (NVC). KIR channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC‐KIR channel function, but whether oxidative stress or inflammation explains this impairment remains elusive. Experimental Approach We evaluated KIR channel function in intact and EC‐denuded pial arteries of wild‐type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid β‐induced oxidative stress seen in AD) or a constitutively active form of TGF‐β1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti‐inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo. Key Results: Our findings show that (i) KIR channel‐mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) KIR channel dysfunction results from KIR2.1 subunit impairment; (iii) about 50% of K+‐induced artery dilatation is mediated by EC‐KIR channels; (iv) oxidative stress and inflammation impair KIR channel function, which can be restored by antioxidant and anti‐inflammatory drugs; and (v) inflammation induces KIR2.1 overexpression and impairs NVC in TGF mice. Conclusion and Implications: Therapies targeting both oxidative stress and inflammation are necessary for full recovery of KIR2.1 channel function in cerebrovascular pathology caused by AD and CVD. [ABSTRACT FROM AUTHOR]