Aspartate Release and Signalling in the Hippocampus

Abstract

The Ca(2+)-dependent release of aspartate from hippocampal preparations was first reported 35 years ago, but the functional significance of this process remains uncertain. Aspartate satisfies all the criteria normally required for identification of a CNS transmitter. It is synthesized in nerve terminals, is accumulated and stored in synaptic vesicles, is released by exocytosis upon nerve terminal depolarization, and activates postsynaptic NMDA receptors. Aspartate may be employed as a neuropeptide-like co-transmitter by pathways that release either glutamate or GABA as their principal transmitter. Aspartate mechanisms include vesicular transport by sialin, vesicular content sensitive to glucose concentration, release mainly outside the presynaptic active zones, and selective activation of extrasynaptic NR1-NR2B NMDA receptors. Possible neurobiological functions of aspartate in immature neurons include activation of cAMP-dependent gene transcription and in mature neurons inhibition of CREB function, reduced BDNF expression, and induction of excitotoxic neuronal death. Recent findings suggest new experimental approaches toward resolving the functional significance of aspartate release.

An optimized fluorescent probe for visualizing glutamate neurotransmission

“…Titration of purified protein in vitro (Fig. 1b) indicates an affinity of 107 ± 9 μM (s.d., n = 5) for glutamate, and 145 ± 18 μM ( n = 3) for aspartate (which has been identified as a co-neurotransmitter with glutamate in some neurons 24 ), and a pK a of 6.5 in the glutamate-bound and 7.0 in the ligand-free state (Supplementary Fig. 9).…”

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

“…Moreover, we observed that acute D-Asp administration also elicits a transient increase of extracellular L-Asp, without affecting the amount of this L-amino acid in homogenates. To explain this data, we suggest that abnormal accumulation of D-Asp in the brain may perturb one or more of the still unclear cellular mechanisms regulating the local racemization of D-Asp into L-Asp2829, L-Asp vesicular storage3031 and release32. In addition, we cannot exclude that non-physiological, high D-Asp extracellular concentration may displace L-Asp from its binding to L-Glu/L-Asp transporters, which regulate the uptake of both Asp enantiomers33, thus resulting in increased extracellular L-Asp levels.…”

Increased extracellular levels of glutamate in the hippocampus of chronically epileptic rats

“…* p < 0.05, one-way ANOVA plus Dunnett's test (A) or Holm-Sidak t test (B). (Gundersen, 2008;Nadler, 2011 …”