Age-Dependent Contributions of NMDA Receptors and L-Type Calcium Channels to Long-Term Depression in the Piriform Cortex

Abstract

In the hippocampus, the contributions of N-methyl-D-aspartate receptors (NMDARs) and L-type calcium channels (LTCCs) to neuronal transmission and synaptic plasticity change with aging, underlying calcium dysregulation and cognitive dysfunction. However, the relative contributions of NMDARs and LTCCs in other learning encoding structures during aging are not known. The piriform cortex (PC) plays a significant role in odor associative memories, and like the hippocampus, exhibits forms of long-term synaptic plasticity. Here, we investigated the expression and contribution of NMDARs and LTCCs in long-term depression (LTD) of the PC associational fiber pathway in three cohorts of Sprague Dawley rats: neonatal (1–2 weeks), young adult (2–3 months) and aged (20–25 months). Using a combination of slice electrophysiology, Western blotting, fluorescent immunohistochemistry and confocal imaging, we observed a shift from an NMDAR to LTCC mediation of LTD in aged rats, despite no difference in the amount of LTD expression. These changes in plasticity are related to age-dependent differential receptor expression in the PC. LTCC Cav1.2 expression relative to postsynaptic density protein 95 is increased in the associational pathway of the aged PC layer Ib. Enhanced LTCC contribution in synaptic depression in the PC may contribute to altered olfactory function and learning with aging.

Noradrenergic Modulation of the Piriform Cortex: A Possible Avenue for Understanding Pre-Clinical Alzheimer’s Disease Pathogenesis

“…Recently, we demonstrated that similar to the hippocampus, there is an age-dependent increase in the contribution of LTCCs to LTD in the PC, concurrent with a decreased role for NMDARs (Rajani et al, 2021). Moreover, inhibition of LTCCs in the aging piriform cortex blocks LTD (Rajani et al, 2021) and could enhance learning (Maziar et al, 2022). The increased significance of LTCCs during aging may provide some insight into the susceptibility of the aged PC to AD-related changes of the LC-NE pathway (Figure 3).…”

“…LTCCs are downstream of β-adrenergic receptors, via a G s -mediated cAMP-PKA pathway to produce an increase in Ca 2+ influx and CREB-mediated protein synthesis and the initiation of long-term memory formation (Ghosh et al, 2017a;Man et al, 2020). Recently, we demonstrated that similar to the hippocampus, there is an age-dependent increase in the contribution of LTCCs to LTD in the PC, concurrent with a decreased role for NMDARs (Rajani et al, 2021). Moreover, inhibition of LTCCs in the aging piriform cortex blocks LTD (Rajani et al, 2021) and could enhance learning (Maziar et al, 2022).…”

“…LTP can also be produced by cooperative weak stimulation of separate associative fiber populations, or by co-activation of both afferent and intrinsic associative fibers in the presence of GABA A inhibitors (Kanter and Haberly, 1993). With low frequency stimulation, long term depression (LTD) can also be induced and contributes to network stability following olfactory based learning (Lebel et al, 2001;Quinlan et al, 2004;Rajani et al, 2021 see Figure 1B for a summary of different types of synaptic plasticity). Afferent-mediated synaptic plasticity, however, seems limited to early developmental stages while associative plasticity persists in adult and aging rodents and may be modified by disease, aging, and learning states (Lebel et al, 2001;Poo and Isaacson, 2007;Rajani et al, 2021).…”

Modulation of L-type calcium channels in Alzheimer’s disease: A potential therapeutic target

“…This age-related modification of the expression and function of LTCCs in hippocampal neurons could contribute to dysregulated calcium homeostasis, resulting in synaptic dysfunction and cognitive decline [115] , although a protective role of increased LTCC plasticity in aging has also been proposed [19] , [92] . Recently, we demonstrated that similarly to the hippocampus [19] , [92] , [134] , there is an age-dependent increase in the contribution of LTCCs to LTD in the piriform cortex (PC), concurrent with a decreased role for NMDARs [129] . Moreover, inhibition of LTCCs in the aged PC blocks LTD [129] and could consequently enhance learning [107] .…”

“…Recently, we demonstrated that similarly to the hippocampus [19] , [92] , [134] , there is an age-dependent increase in the contribution of LTCCs to LTD in the piriform cortex (PC), concurrent with a decreased role for NMDARs [129] . Moreover, inhibition of LTCCs in the aged PC blocks LTD [129] and could consequently enhance learning [107] . LTCC dysregulation is suggested in models for age-related cognitive decline [157] and is likely involved in AD.…”