The mechanisms shaping CA2 pyramidal neuron action potential bursting induced by muscarinic acetylcholine receptor activation

Abstract

Recent studies have revealed that hippocampal area CA2 plays an important role in hippocampal network function. Disruption of this region has been implicated in neuropsychiatric disorders. It is well appreciated that cholinergic input to the hippocampus plays an important role in learning and memory. While the effect of elevated cholinergic tone has been well studied in areas CA1 and CA3, it remains unclear how changes in cholinergic tone impact synaptic transmission and the intrinsic properties of neurons in area CA2. In this study, we applied the cholinergic agonist carbachol and performed on-cell, whole-cell, and extracellular recordings in area CA2. We observed that under conditions of high cholinergic tone, CA2 pyramidal neurons depolarized and rhythmically fired bursts of action potentials. This depolarization depended on the activation of M1 and M3 cholinergic receptors. Furthermore, we examined how the intrinsic properties and action-potential firing were altered in CA2 pyramidal neurons treated with 10 µM carbachol. While this intrinsic burst firing persisted in the absence of synaptic transmission, bursts were shaped by synaptic inputs in the intact network. We found that both excitatory and inhibitory synaptic transmission were reduced upon carbachol treatment. Finally, we examined the contribution of different channels to the cholinergic-induced changes in neuronal properties. We found that a conductance from Kv7 channels partially contributed to carbachol-induced changes in resting membrane potential and membrane resistance. We also found that D-type potassium currents contributed to controlling several properties of the bursts, including firing rate and burst kinetics. Furthermore, we determined that T-type calcium channels and small conductance calcium-activated potassium channels play a role in regulating bursting activity.

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

“…Because theta rhythm is a brain state characterized by elevated levels of acetylcholine, we approximately mimicked these conditions in the hippocampal slice preparation by bath application of 10 µM of the cholinergic agonist carbachol (CCh). Under these conditions, CA2 PNs depolarize and spontaneously fire rhythmic bursts of APs, and the properties of these AP bursts are tightly controlled by excitatory and inhibitory synaptic transmission ( Robert et al, 2020 ). Thus, we decided to examine how SuM input stimulation influenced CA2 PN firing under these conditions.…”

“…In the presence of CCh, CA2 PNs undergo a depolarization of the membrane potential that is followed by a period of AP firing as the membrane potential remains depolarized for several seconds, and then slowly hyperpolarizes until the next bursting event ( Robert et al, 2020 ). We observed that photostimulation of SuM inputs resulted in a striking reduction in the amount of time the membrane potential remained depolarized, and this is likely why the burst duration was significantly shorter in bursts with SuM photo-stimulation ( Figure 7F–G ; burst duration was 4.0 ± 1.1 s in control and 1.6 ± 0.5 s with photostimulation, n = 7; paired-T test, p=0.037).…”

“…While area CA2 has been shown to play a significant role in several hippocampal processes including social memory formation ( Hitti and Siegelbaum, 2014 ; Stevenson and Caldwell, 2014 ) sharp-wave ripple generation ( Oliva et al, 2016a ) and spatial encoding ( Kay et al, 2016 ), information about the local circuitry and cellular mechanisms allowing these functions is lacking. There is mounting evidence that generalizations cannot be made from the rich understanding of areas CA1 and CA3, as neurons in area CA2 have been shown to have unique molecular expression profiles ( Cembrowski et al, 2016 ; Lein et al, 2004 ), morphology ( Bartesaghi and Ravasi, 1999 ; Nò, 1934 ) and cellular properties ( Robert et al, 2020 ; Srinivas et al, 2017 ; Sun et al, 2014 ). Notably, and in contrast to area CA1, CA2 pyramidal neurons do not undergo high-frequency stimulation-induced synaptic plasticity ( Dasgupta et al, 2020 ; Zhao et al, 2007 ).…”

Cholinergic transmission from the basal forebrain modulates social memory in male mice

“…Interestingly, mice with genetically inactivated CA2 pyramidal neurons, also showed an inability to differentiate between novel and familiar conspecifics (Hitti & Siegelbaum, 2014). Noteworthy, cholinergic signalling has been shown to impact synaptic transmission and the intrinsic properties of CA2 neurons (Robert et al, 2020).…”

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

“…While area CA2 has been shown to play a significant role in several hippocampal processes including social memory formation (Hitti and Siegelbaum, 2014;Stevenson and Caldwell, 2014) sharp-wave ripple generation (Oliva et al, 2016) and spatial encoding (Kay et al, 2016), information about the local circuitry and cellular processes allowing these functions is lacking. There is mounting evidence that generalizations cannot be made from the rich understanding of areas CA1 and CA3, as neurons in area CA2 have been shown to have unique molecular expression profiles (Cembrowski et al, 2016;Lein et al, 2004), morphology (Bartesaghi and Ravasi, 1999;No, 1934) and cellular properties (Robert et al, 2020;Srinivas et al, 2017;Sun et al, 2014). Notably, and in contrast to area CA1, CA2 pyramidal neurons do not undergo NMDA-mediated synaptic plasticity (Dasgupta et al, 2020;Zhao et al, 2007).…”