Norepinephrine and the dentate gyrus

Norepinephrine's role in the dentate gyrus is assessed based on a review of what is known about its innervation and receptor patterns and its functional effects at both cellular and behavioral levels. The data support seven hypotheses: (1) Norepinephrine's functional actions are primarily mediated by beta adrenoceptors and include electrophysiological enhancement of responses to excitatory input and glycogenolytic metabolic support of excitatory synaptic activity. (2) At the cellular level, locus coeruleus burst release of norepinephrine transiently inhibits feedforward interneurons and either excites or inhibits subpopulations of feedback interneurons. Consistent with reduced feedforward inhibition, granule cell firing is transiently increased. Concomitant EEG effects include transient increases in theta power and decreases in beta and gamma power. (3) Norepinephrine selectively promotes the processing of medial perforant path spatial input. This effect is mediated both through short- and long-term potentiation of cell excitability and through delayed potentiation of synaptic input. A critical level of norepinephrine release is required for long-term effects to norepinephrine alone. Norepinephrine release switches early phase frequency-induced long-term potentiation of perforant path input to an enduring late phase form and can reinstate decayed long-term potentiation. Norepinephrine also promotes frequency-induced potentiation of granule cell output at the mossy fiber to CA3 connection. (4) Local increases in norepinephrine accompany glutamate release and release of other neurotransmitters providing a mechanism for norepinephrine enhancement effects independent of locus coeruleus firing. (5) Stimuli, such as novelty and reward and punishment, which activate locus coeruleus neurons, enhance responses to medial perforant path input and engage late phase frequency-induced long-term potentiation through beta adrenoceptor activation. (6) Behavioral studies are consistent with the mechanistic evidence for a norepinephrine role in promoting learning and memory and assisting retrieval. (7) The overall profile suggests lower levels of norepinephrine may facilitate pattern completion or memory retrieval while higher levels would recruit global remapping and promote long-term episodic memory.