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

Information and action coding by cortical circuits relies on a balanced dialogue between excitation and inhibition. Circuit hyperexcitability is considered a potential pathophysiological mechanism in various brain disorders, but the underlying deficits, especially at early disease stages, remain largely unknown. We report that asymptomatic female mice carrying the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which represents a high-prevalence genetic abnormality for human amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) spectrum disorder, exhibit abnormal motor cortex output. The number of primary motor cortex (M1) layer 5 pyramidal neurons is reduced in asymptomatic mice, with the surviving neurons receiving a decreased inhibitory drive that results in a higher M1 output, specifically during high-speed animal locomotion. Importantly, using deep-learning algorithms revealed that speed-dependent M1 output predicts the likelihood of C9orf72 genetic expansion. Our data link early circuit abnormalities with a gene mutation in asymptomatic ALS/FTLD carriers.

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

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.

Input-Specific Synaptic Location and Function of the α5 GABAA Receptor Subunit in the Mouse CA1 Hippocampal Neurons.

Hippocampus-dependent learning processes are coordinated via a large diversity of GABAergic inhibitory mechanisms. The α5 subunit-containing GABAA receptor (α5-GABAAR) is abundantly expressed in the hippocampus populating primarily the extrasynaptic domain of CA1 pyramidal cells, where it mediates tonic inhibitory conductance and may cause functional deficits in synaptic plasticity and hippocampus-dependent memory. However, little is known about synaptic expression of the α5-GABAAR and, accordingly, its location site-specific function. We examined the cell- and synapse-specific distribution of the α5-GABAAR in the CA1 stratum oriens/alveus (O/A) using a combination of immunohistochemistry, whole-cell patch-clamp recordings and optogenetic stimulation in hippocampal slices obtained from mice of either sex. In addition, the input-specific role of the α5-GABAAR in spatial learning and anxiety-related behavior was studied using behavioral testing and chemogenetic manipulations. We demonstrate that α5-GABAAR is preferentially targeted to the inhibitory synapses made by the vasoactive intestinal peptide (VIP)- and calretinin-positive terminals onto dendrites of somatostatin-expressing interneurons. In contrast, synapses made by the parvalbumin-positive inhibitory inputs to O/A interneurons showed no or little α5-GABAAR. Inhibiting the α5-GABAAR in control mice in vivo improved spatial learning but also induced anxiety-like behavior. Inhibiting the α5-GABAAR in mice with inactivated CA1 VIP input could still improve spatial learning and was not associated with anxiety. Together, these data indicate that the α5-GABAAR-mediated phasic inhibition via VIP input to interneurons plays a predominant role in the regulation of anxiety while the α5-GABAAR tonic inhibition via this subunit may control spatial learning.SIGNIFICANCE STATEMENT The α5-GABAAR subunit exhibits high expression in the hippocampus, and regulates the induction of synaptic plasticity and the hippocampus-dependent mnemonic processes. In CA1 principal cells, this subunit occupies mostly extrasynaptic sites and mediates tonic inhibition. Here, we provide evidence that, in CA1 somatostatin-expressing interneurons, the α5-GABAAR subunit is targeted to synapses formed by the VIP- and calretinin-expressing inputs, and plays a specific role in the regulation of anxiety-like behavior.