Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation

Abstract

Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We previously found that age-related enhancement of Ca(2+) buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, and Griffith WH. J Neurophysiol 102: 2194-2207, 2009). One way that altered Ca(2+) buffering could contribute to cognitive impairment involves synaptic function. In this report we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous postsynaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole cell patch-clamp recording, we show that sPSCs and miniature PSCs are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (4-7 mo) and aged (22-24 mo) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca(2+) buffering. We also show that increasing Ca(2+) buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons.

Medial prefrontal-perirhinal cortical communication is necessary for flexible response selection

“…The observation that a contralateral deficit impaired performance on the OPPA task, which requires flexibility in selecting the correct object based on spatial location, but not the control tasks, is interesting in the context of aging and disease. The PER (Burke, Ryan, and Barnes, 2012c; Khan, Liu, Provenzano, Berman, Profaci, Sloan, et al, 2014; Reagh, Ho, Leal, Noche, Chun, Murray, et al, 2015; Ryan, Cardoza, Barense, Kawa, Wallentin-Flores, Arnold, et al, 2012) and mPFC (Griffith, Dubois, Fincher, Peebles, Bizon, and Murchison, 2014; Morrison and Baxter, 2012) are among the most vulnerable brain regions to age-related dysfunction. Even when these areas are compromised, however, aged animals are still able to perform object discriminations and differentiate the left from right side (Beas et al, 2013; Burke, Wallace, Hartzell, Nematollahi, Plange, and Barnes, 2011; Hernandez et al, 2015).…”

Effects of ethanol and varenicline on female Sprague-Dawley rats in a third trimester model of fetal alcohol syndrome

“…2C, bottom). Although BF neurons receive both excitatory and inhibitory inputs, BF synaptic transmission is dominated by GABAergic IPSCs as reported previously (Griffith, Dubois et al 2014). In these experiments, approximately 90% of all synaptic transmission was GABA A R-mediated.…”

“…To isolate GABA A R-mediated postsynaptic currents, D(−)2-amino-5-phosphonovaleric acid (APV, 40 µM, Sigma) and 6,7-dinitroquinoxaline-2,3-dione (DNQX, 10 µM, Sigma) were added to the perfusion solution. Spontaneous synaptic currents were analyzed using MiniAnalysis 6.0.3 (Synaptosoft) as described previously (DuBois, Parrish et al 2004, DuBois, Damborsky et al 2013, Wang, Dubois et al 2013, Griffith, Dubois et al 2014). Analysis of the electrophysiological data was conducted blind with respect to treatment.…”

DHA Supplementation Alone or in Combination with Other Nutrients Does not Modulate Cerebral Hemodynamics or Cognitive Function in Healthy Older Adults

“…Dietary DHA is also know to modulate a number of neurotransmitter systems including the cholinergic system [ 25 ], which is known to play a key role in memory and learning [ 26 ] and the degradation of which is associated with the typical cognitive deficits observed in normal and pathological aging [ 27 , 28 ]. One group of researchers also demonstrated a role for cholinergic neurotransmission in the regulation of the neurovascular coupling of brain activity and local cerebral blood flow in aged monkeys [ 29 ], and subsequently demonstrated that the age-impaired regional cerebral blood flow (rCBF) response to tactile stimulation was positively modulated following four weeks’ dietary supplementation with 150 mg/kg/day DHA [ 30 ].…”