The Role of AMPARs in the Maturation and Integration of Caudal Ganglionic Eminence-Derived Interneurons into Developing Hippocampal Microcircuits

Abstract

In the hippocampal CA1, caudal ganglionic eminence (CGE)-derived interneurons are recruited by activation of glutamatergic synapses comprising GluA2-containing calcium-impermeable AMPARs and exert inhibitory regulation of the local microcircuit. However, the role played by AMPARs in maturation of the developing circuit is unknown. We demonstrate that elimination of the GluA2 subunit (GluA2 KO) of AMPARs in CGE-derived interneurons, reduces spontaneous EPSC frequency coupled to a reduction in dendritic glutamatergic synapse density. Removal of GluA1&2&3 subunits (GluA1-3 KO) in CGE-derived interneurons, almost completely eliminated sEPSCs without further reducing synapse density, but increased dendritic branching. Moreover, in GluA1-3 KOs, the number of interneurons invading the hippocampus increased in the early postnatal period but converged with WT numbers later due to increased apoptosis. However, the CCK-containing subgroup increased in number, whereas the VIP-containing subgroup decreased. Both feedforward and feedback inhibitory input onto pyramidal neurons was decreased in GluA1-3 KO. These combined anatomical, synaptic and circuit alterations, were accompanied with a wide range of behavioural abnormalities in GluA1-3 KO mice compared to GluA2 KO and WT. Thus, AMPAR subunits differentially contribute to numerous aspects of the development and maturation of CGE-derived interneurons and hippocampal circuitry that are essential for normal behaviour.

Identification of Neurensin-2 as a novel modulator of emotional behavior

“…Indeed, SMARCA3 cKO mice had a dramatic decrease in AMPAR signaling in CCK interneurons, a similar effect to the one we observed in social defeat stress model. In line with our data, a recent study reported that the deletion of AMPAR subunits from caudal ganglionic eminence-derived interneurons resulted in anxiety-like behavior [30]. The glutamatergic signaling in interneurons becomes increasingly associated with depressive disorders and their treatments [31,32].…”

“…Such frequency changes in hippocampal caudal ganglionic eminence-derived neurons were also observed when AMPAR subunits were deleted. Theses frequency changes were also accompanied by anxiety-like behaviors [30]. Therefore, SMARCA3/Neurensin-2 modulation of AMPAR frequency in CCK neurons may mediate impairments in emotional behavior.…”

Loss ofGrin2aCauses a Transient Delay in the Electrophysiological Maturation of Hippocampal Parvalbumin Interneurons: A Possible Mechanism for Transient Seizure Burden in Patients with NullGRIN2AVariants

“…As previously reported, mIPSCs onto pyramidal cells are largely from basket cell interneuron activity, which in the hippocampus arises from approximately equal contributions from PV and CCK basket cells (Soltesz, Smetters et al 1995, Akgul, Abebe et al 2019). In order to probe PV cell-specific activity, we bath applied DAMGO, a specific mu-opioid receptor agonist (Onogi, Minami et al 1995).…”

“…NMDARs are found on both PV and CCK cells, however, recent reports suggest that CCK cells express less GluN2A than their PV cell counterparts (Matta, Pelkey et al 2013, Perszyk, DiRaddo et al 2016, Booker, Sumera et al 2021). Additionally, CCK cell density is reportedly influenced by 5-HT 3A and AMPA receptor-mediated activity (Murthy, Niquille et al 2014, Akgul, Abebe et al 2019). Despite having a higher overall synaptic NMDA:AMPA, perhaps CCK cells rely on electrical cues from non-NMDARs to control apoptotic pathways (Bortone and Polleux 2009, Matta, Pelkey et al 2013).…”

Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence

“…Further, expression of AMPAR subunits follows a distinct ontogenetic pattern, which suggests specific functional roles at different periods during development. In the rat hippocampus, GluA1 expression remains constant until young adulthood, whereas GluA3 increases, and both GluA2 and GluA4 expressions are reduced over time[ 156 ], with GluA2 expression mostly limited to interneurons[ 157 ]. Within the VTA, electrophysiological evidence has suggested that GluA2-lacking AMPARs are abundant during the first postnatal days with a reduction in functional presence across age, with similar findings in cortical pyramidal cells and other brain areas[ 158 - 160 ].…”