Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors

Abstract

Young (3-6 months) and middle-age (10 -14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline.

Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence

“…We confirmed that performance on an attention task, which depends on the PFC, is impaired in middle-age rats (Guidi et al, 2015). NMDAR blockade produced a dose-dependent, biphasic enhancement in measures of attention for conditions that tax attentional demand.…”

“…Behavioral training of animals on 5-CSRTT was conducted as previously published (Guidi et al, 2015). Testing was conducted in two identical standard rat testing chambers (30.5 × 25.4 × 30.5 cm; Coulbourn Instruments, Allentown, PA) with metal front and back walls, and transparent Plexiglas sidewalls.…”

“…In the case of aging, cognitive decline is associated with altered Ca 2+ regulation and impaired synaptic function, including a decrease in the function of N -methyl-D-aspartate receptors (NMDARs) (Foster and Norris, 1997; Foster, 2007, 2012). The emergence of deficits in episodic memory and executive function are linked to decrease in the NMDAR-mediated synaptic responses in the hippocampus and prefrontal cortex (PFC), respectively (Foster and Norris, 1997; Foster, 2012; Kumar and Foster, 2013; Guidi et al, 2015). Similarly, β-amyloid (Aβ) impairs synaptic plasticity (Walsh et al, 2002; Shankar et al, 2007; Shankar et al, 2008) and rapidly decreases NMDAR responses (Snyder et al, 2005; Lacor et al, 2007; Dewachter et al, 2009), which may contribute to the onset of memory deficits associated with the early stages of Alzheimer’s disease.…”

Potential synergistic action of 19 schizophrenia risk genes in the thalamus

“…Such damage has been found to be significantly increased in patients with early onset first psychotic episodes (Micó et al, 2011). Given that NMDARs are strongly inhibited by oxidation, disruption of these genes can produce NMDAR hypofunction (Bodhinathan et al, 2010; Guidi et al, 2015) and thereby increase delta.…”

Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators

“…Shankar et al suggested that A β oligomers decreased the density of dendritic spines, NMDAR-mediated calcium influx, and internalization of synaptic NMDARs [44, 45]. Moreover, APP or ApoE4 mutant mice exhibit a decrease in NMDAR-mediated synaptic responses and impaired LTP; NMDAR hypofunction with advanced age is closely tied to redox state in the CNS [46]. However, in targeting NMDARs, only memantine has been approved by the FDA currently.…”