Differential Regulation of NMDA Receptor-Mediated Transmission by SK Channels Underlies Dorsal-Ventral Differences in Dynamics of Schaffer Collateral Synaptic Function

Abstract

Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, we investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses in the mouse hippocampus. We find that, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to frequency patterns of stimulation. In contrast to dorsal hippocampus, frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. Our results indicate that all these differences in postsynaptic function are due to an enhanced activation of SK-type K ϩ channels that suppresses NMDAR-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, our findings indicate that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing, and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors.

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso‐ventral axis is inversely related to the expression levels of plasticity‐related neurotransmitter receptors

“…In agreement with this suggestion, a recent study showed that pyramidal neurons of the ventral CA1 region express significantly higher levels of Ca 2+ ‐activated SK‐type K + channels. These, in turn, were shown to inhibit NMDAR‐dependent EPSP amplification to a greater degree in the ventral as opposed to the DH (Babiec, Jami, Guglietta, Chen, & O'Dell, ).…”

“…Thus, although GluN2A expression was equivalent across the dorsal, intermediate and ventral CA1 regions, the graded expression of GluN2B‐containing NMDARs can be expected to impact on LTP responses, as it will serve to alter the GluNA/GluN2B ratios across the dorsoventral axis. Additionally, an enhanced SK‐type K+ channel‐dependent suppression of NMDAR activation in ventral CA1 pyramidal cells, as opposed to dorsal CA1 pyramidal cells (Babiec et al, ), would be expected to escalate the propensity differences of hippocampal parts in expressing long‐term synaptic potentiation. LTP maintenance is supported by mGlu5 (Mukherjee and Manahan‐Vaughan, ) and this receptor also potentiates NMDAR currents (Doherty, Palmer, Henley, Collingridge, & Jane, ; Perroy et al, ).…”

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

“…LTP is a basic synaptic model of learning and memory (Martin and Morris, ) and it is typically induced at hippocampal synapses (Bliss, Collingridge, & Morris, ). The ability of hippocampal synapses for LTP, however, is not evenly distributed along the dorsoventral axis of the hippocampus (Babiec, Jami, Guglietta, Chen, & O'Dell, ; Colgin, Kubota, Jia, Rex, & Lynch, ; Grigoryan, Korkotian, & Segal, ; Kouvaros and Papatheodoropoulos, ; Maruki, Izaki, Nomura, & Yamauchi, ; Milior et al, ; Moschovos, Kostopoulos, & Papatheodoropoulos, ; Papatheodoropoulos and Kostopoulos, ; Schreurs, Sabanov, & Balschun, ). On the contrary, the difference in LTP emblematically represents the recently emerging concept of intrinsic diversification along the dorsoventral axis of the hippocampus, recently reviewed in (Papatheodoropoulos, ; Tushev and Schuman, ).…”

Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus

“…Interestingly, SK channel expression is higher in the vHC than the dHC and these channels buffer glutamatergic synaptic activity to a greater extent in the vHC (Babiec et al, 2017). This differential distribution of SK channels may partly explain the differential effects of CIE on synaptic transmission along the dorsal-ventral axis of the hippocampus While CIE is a well-validated rodent model of AUD, there are many parallels between the maladaptive behavioral phenotypes promoted by this model and models of stress (Holmes et al, 2012;Morales et al, 2018Morales et al, , 2015.…”