Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging

Abstract

Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan. Our data showed that while the number and morphological features of I-S3 cells remained unchanged, their firing and synaptic properties were significantly altered in old animals. In particular, the action potential duration and the level of steady-state depolarization were significantly increased in old animals in parallel with a significant decrease in the maximal firing frequency. Reducing the fast-delayed rectifier potassium or transient sodium conductances in I-S3 cell computational models could reproduce the age-related changes in I-S3 cell firing properties. However, experimental data revealed no difference in the activation properties of the Kv3.1 and A-type potassium currents, indicating that transient sodium together with other ion conductances may be responsible for the observed phenomena. Furthermore, I-S3 cells in aged mice received a stronger inhibitory drive due to concomitant increase in the amplitude and frequency of spontaneous inhibitory currents. These age-associated changes in the I-S3 cell properties occurred in parallel with an increased inhibition of their target interneurons and were associated with spatial memory deficits and increased anxiety. Taken together, these data indicate that VIP+/CR+ interneurons responsible for local circuit disinhibition survive during aging but exhibit significantly altered physiological properties, which may result in the increased inhibition of hippocampal interneurons and distorted mnemonic functions.

Effects of Aging on the Structure and Expression of NMDA Receptors of Somatostatin Expressing Neurons in the Mouse Hippocampus

“…In the visual cortex, the dendritic arbors of interneurons (in general) were simplified in aged mice ( Eavri et al, 2018 ). However, in other specific interneuronal types, such as the vasoactive intestinal peptide/calretinin-expressing cells in the CA1 region of the hippocampus, no differences were found in dendritic length or number of intersections between young and old mice ( Francavilla et al, 2020 ). However, it has to be noted that we have observed changes in the dendritic spine density only in 9-month females and when grouping both sexes.…”

Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion

“…Acute brain slices were prepared from P42-90 mice as previously described (Magnin et al, 2019;Francavilla et al, 2020;Luo et al, 2020). Briefly, animals were deeply anaesthetized with a ketamine-xylazine mixture (ketamine: 100 mg/kg, xylazine: 10 mg/kg) and perfused intracardially with ice-cold sucrose solution (20 mL) containing (in mM): 250 sucrose, 2 KCl, 1.25 NaH 2 PO 4 , 26 NaHCO 3 , 7 MgSO 4 , 0.5 CaCl 2 , and 10 glucose.…”

Altered firing output of VIP interneurons and early dysfunctions in CA1 hippocampal circuits in the 3xTg mouse model of Alzheimer’s disease

“…Nevertheless, investigations into the activity profiles and local synaptic communication among CA1 INs of 3xTg-AD mice in vivo have been lacking. Importantly, prior studies on aged mice have identified significant changes in firing properties of type 3 interneuron-specific interneurons (I-S3), which co-express CR and VIP and control the activity of SOM-INs but also of PV-INs in the CA1 hippocampal region (Tyan et al, 2014; Francavilla et al, 2020; Luo et al, 2020). Whether impairments in I-S3 activity might contribute to altered CA1 inhibition and network function in 3xTg-AD mice remains unknown.…”