Direct excitation of parvalbumin‐positive interneurons by M₁ muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition

Abstract

Key pointsr Parvalbumin-containing (PV) neurons from mouse CA1 hippocampus (HC) and prefrontal cortex exhibit a fast spiking phenotype in vitro. Within CA1, HC PV cells are mainly comprised of basket and bistratified cell types.r Direct activation of muscarinic acetylcholine receptors (mAChRs) enhances excitability more in CA1 HC than in prefrontal cortex PV cells. r In vivo activation of M 1 mAChRs in PV cells is important in recognition and working memory but not spatial memory.Abstract Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M 1 mAChRs genetically from PV interneurons, we created PV- Finally, relative to wild-type controls, PV-M 1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M 1 mAChRs on PV cells contributes to some forms of learning and memory.

Muscarinic excitation of parvalbumin‐positive interneurons contributes to the severity of pilocarpine‐induced seizures

“…11 In a representative PV-YFP cell (Fig. 4A,B), spontaneous firing was observed under baseline conditions (Fig.…”

“…This modulation included an increase in AP frequency, conversion of the post-spike afterhyperpolarization to an afterdepolarization, and an increase holding current at −60 mV. 11,12 …”

“…AAVs were injected into the ventral CA1 (anteroposterior: 2.8 mm, mediolateral: 3.3 mm, dorsoventral: 2.3 mm) of adult PV-CRE or PV-M 1 KO mice (>8 weeks of age); PV-YFP or hM3Dq-mCherry-positive (PV-mCherry) cells were visualized in acute hippocampal slices from PV-M 1 KO or PV-CRE mice, respectively, at least 4 weeks after surgery. 11 …”

“…During hM3Dq-mCherry activation, the level of depolarization was calculated based on a linear regression between the first derivative of the AP and V m . 11 Intrinsic membrane properties were measured as described previously. 11 …”

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…However, it is also possible that M 1 activation could induce changes in cortical network properties, leading to an overall depression in the PFC output. It is known that M 1 activation can enhance excitability in the GABAergic interneurons of the PFC (Yi et al, 2014), and it is conceivable that M 1 activation by high concentrations of CCh or a combination of the M 1 PAM VU0453595 and CCh leads to a long-term enhancement of GABAergic interneuron-mediated inhibitory tone in the PFC and thereby leads to sustained depression of the excitatory output in PFC. Hence, the loss in mLTD in the PCP-treated mice could be related to a dysfunction in the muscarinic regulation of GABAergic neurotransmission in the PFC.…”