No abstract

Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain. In higher cortical structures such as the hippocampus, norepinephrine, via ␤ adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory. In this study, we investigated the effect of ␤1AR activation on hippocampal cornu ammonis 3 (CA3) network activity. AR expression was first determined using immunocytochemistry with antibodies against ␤1ARs, which were found to be exceptionally dense in hippocampal CA3 pyramidal neurons. CA3 network activity was then examined in vitro using field potential recordings in rat brain slices. The selective ␤AR agonist isoproterenol caused an enhancement of hippocampal CA3 network activity, as measured by an increase in frequency of spontaneous burst discharges recorded in the CA3 region. In the presence of ␣AR blockade, concentration-response curves for isoproterenol, norepinephrine, and epinephrine suggested that a ␤1AR was involved in this response, and the rank order of potency was isoproterenol Ͼ norepinephrine ϭ epinephrine. Finally, equilibrium dissociation constants (pK b ) of subtype-selective ␤AR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity. The selective ␤1AR antagonists atenolol and metoprolol blocked isoproterenol-induced enhancement, with apparent K b values of 85 Ϯ 36 and 3.9 Ϯ 1.7 nM, respectively. In contrast, the selective ␤2AR antagonists ICI-118,551 and butoxamine inhibited isoproterenol-mediated enhancement with apparent low affinities (K b of 222 Ϯ 61 and 9268 Ϯ 512 nM, respectively). Together, this pharmacological profile of subtype-selective ␤AR antagonists indicates that in this model, ␤1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.

A major target of the adrenergic system is the hippocampus, a region that is critical for learning and memory. Recent studies suggest alpha‐1A adrenergic receptors (α1A‐ARs) may regulate neurogenesis and neuronal differentiation. Our understanding of the function of α1A‐ARs is limited due to a lack of specific ligands and antibodies. To address this, transgenic mice were generated which over‐express the α1A‐AR with enhanced green fluorescent protein (EGFP) or constitutively active mutant (CAM) α1A‐AR. Knockout (KO) α1A mice were also generated. Immunohistochemistry showed that CAM α1A‐AR mice had increased BrdU incorporation compared to normal and KO α1A‐AR mice. Increased numbers of hippocampal interneurons in CAM α1A mice compared to normal mice were also observed. Increased interneurons may affect learning and memory. Normal, CAM α1A, and KO α1A mice were tested on a multi‐component T‐maze and the Morris water maze. CAM α1A mice displayed increased cognitive ability in the T‐maze and the Morris water maze compared to normal mice. In both models, KO α1A‐AR mice displayed the worst cognitive ability. Treating normal mice with the selective α1A‐AR agonist cirazoline also showed enhanced learning and memory processes. Stimulation of α1A‐ARs may offer a new therapeutic strategy for increasing cognitive function and treating neurodegenerative diseases. Supported by NIH, NIH COBRE, NSF ND EPSCoR, NSF CAREER.

No abstract

Adrenergic receptors (ARs) have been shown to regulate neuronal function in diverse ways, from altering membrane potential and transmitter release to effects on gene expression. Activation of α1ARs produces a membrane depolarization in a specific subset of hippocampal interneurons. Evidence from transgenic mice either lacking (KO) or overexpressing (CAM) α1A or α1BARs suggests that the majority of this response is due to activation of α1AARs. Electrophysiological recordings during application of α1AR agonists produced a concentration‐dependent increase in action potential frequency in hippocampal interneurons from normal and α1BAR KO mice, but not α1AAR KO mice. α1AR agonists also increased the frequency and amplitude of IPSCs in CA1 pryamidal neurons. Mice overexpressing α1AARs showed increased hippocampal interneuron density. BrdU immunohistochemistry revealed enhanced neurogenesis in CAM α1AAR animals. This result was also observed in normal mice treated with the α1AAR agonist, cirazoline. Furthermore, when compared to controls, CAM α1AAR mice showed an increase in latency periods preceding seizures when exposed to the epileptogenic agent, flurothyl. These findings suggest that activation of α1AARs increases inhibitory tone not only via increased interneuron firing but possibly by increased numbers of interneurons. These findings are potentially very significant as they link α1AAR‐induced proliferation of interneurons to the antiepileptic actions of the adrenergic system. Supported by NIH R01HL61438, NIH COBRE, NSF ND EPSCoR, NSF CAREER, Epilepsy Foundation.