Positive Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal and Cortical Neurons

Abstract

This study investigated whether positive modulators of AMPA-type glutamate receptors influence neurotrophin expression by forebrain neurons. Treatments with the ampakine CX614 markedly and reversibly increased brain-derived neurotrophic factor (BDNF) mRNA and protein levels in cultured rat entorhinal/hippocampal slices. Acute effects of CX614 were dose dependent over the range in which the drug increased synchronous neuronal discharges; threshold concentrations for acute responses had large effects on mRNA content when applied for 3 d. Comparable results were obtained with a second, structurally distinct ampakine CX546. Ampakine-induced upregulation was broadly suppressed by AMPA, but not NMDA, receptor antagonists and by reducing transmitter release. Antagonism of L-type voltage-sensitive calcium channels blocked induction in entorhinal cortex but not hippocampus. Prolonged infusions of suprathreshold ampakine concentrations produced peak BDNF mRNA levels at 12 hr and a return to baseline levels by 48 hr. In contrast, BDNF protein remained elevated throughout a 48 hr incubation with the drug. Nerve growth factor mRNA levels also were increased by ampakines but with a much more rapid return to control levels during chronic administration. Finally, intraperitoneal injections of CX546 increased hippocampal BDNF mRNA levels in aged rats and middle-aged mice. The present results provide evidence of regional differences in mechanisms via which activity regulates neurotrophin expression. Moreover, these data establish that changes in synaptic potency produce sufficient network level physiological effects for inducing neurotrophin genes, indicate that the response becomes refractory during prolonged ampakine exposure, and raise the possibility of using positive AMPA modulators to regulate neurotrophin levels in aged brain.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

“…One hypothesis suggests that an increase in expression of neurotrophic factors such as brain derived neurotrophic factor (BDNF) and a resultant increase in neuroplasticity and protection of neurons from neurotoxic insults may be relevant. Similar to antidepressants, AMPA receptor potentiators have been shown increase the production of BDNF and cell proliferation in the hippocampus (Bai et al, 2003;Lauterborn et al, 2000;Legutko et al, 2001;Mackowiak et al, 2002). Another possibility is modulation of amine neurotransmission.…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…They have been associated with enhanced neurogenesis 228 and increased expression of neurotrophic factors such as BDNF. 229,230 The AMPAkine Ampalex exhibited more rapid effect (during the first week of treatment) than fluoxetine (after 2 weeks). 231 Metabotropic glutamate receptors.…”

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

“…CX1837 crosses the bloodbrain barrier when given systemically, increases excitatory signaling and stimulates an increased release in BDNF. 6,11,12 CX1837 (1 mg/kg, intraperitoneally twice daily) promotes a mild gain of function in the impaired forelimb of the grid-walking task ( Figure 1A; Po 0.05) by week 6 after stroke. No significant gain of function was observed on the cylinder task ( Figure 1B; P40.05) by week 6 after stroke.…”

“…9,10 The ampakine, CX1837, has attracted considerable attention, as it is a positive allosteric modulator of AMPA receptors that under homeostatic conditions stimulates and increases BDNF mRNA and protein levels. 11,12 We have recently showed that CX1837 enhances poststroke functional recovery in young animals. 6 We have also shown that CX1837-mediated functional recovery occurred in a BDNF/TrkB-dependent manner, a finding that has been confirmed by Massa et al who further identified the role of downstream protein kinase B (AKT) and extracellular signalregulated kinase (ERK) signaling pathways.…”