Local and long-range GABAergic circuits in hippocampal area CA1 and their link to Alzheimer's disease

Abstract

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

Keywords: Alzheimer’s disease; GABAergic circuits; disinhibition; hippocampus (CA1); long-range GABAergic neurons.

Figure 1

General GABAergic Circuit Motifs in area CA1. Schematic representations of (A) feed-forward inhibition (FFI) and (B) feed-back inhibition (FBI) in CA1 highlighting the pyramidal neuron (PN, in blue) with the Schaffer Collateral inputs (SC, arrows in black) and the inhibition of local interneurons (IN, in red) in somatic (S) and dendritic (D) compartments. (C) Long-range disinhibition (D) Local disinhibition in hippocampal area CA1.

Figure 2

Hippocampal Formation and area CA1 Circuitry. (A) Schematic representation of coronal section of a rodent brain highlighting the hippocampal region with its sub-areas dentate gyrus (DG), CA3, CA2, and CA1. (B) Stratification of hippocampal area CA1 namely stratum oriens (SO), stratum pyramidale (SP), stratum radiatum (SR), and stratum lacunosum moleculare (SLM). The CA1 pyramidal neuron soma and dendrites organization are shown in blue, and INs in red. Created with BioRender.

Figure 3

Local Inhibitory microcircuits in area CA1. Schematic representation of CA1 microcircuit connectivity, the CA1 pyramidal neuron (blue) is surrounded by local GABAergic microcircuitry: PV⁺ IN (pink), SST⁺ IN (yellow), soma-targeting CCK⁺ basket cell and SR/SLM border CCK IN (light blue), CR⁺ VIP IN (dark purple), CCK⁺ VIP⁺ IN (light purple), and NPY⁺ IN (gray). Excitatory and inhibitory inputs from EC into SLM of area CA1 shown in green and red, respectively. Inhibitory inputs from the Medial septum (MS) into SLM of area CA1 shown in red.

Figure 4

Long-range Inhibitory projections circuits in the hippocampus. Long-range Inhibitory projections (LRIPs) into hippocampal area CA1 and LRIPs outputs from hippocampal area. Inhibition or disinhibition of hippocampal CA1 pyramidal neuron (in blue), with GABAergic inhibitory interneurons (in yellow) and disinhibitory interneurons (in purple). Inputs into hippocampal area CA1 from dentate gyrus granule cells and CA3 pyramidal neurons (in black).

Figure 5

Summary of CA1 INs in health and Alzheimer’s disease. (A) Schematic representation of the hippocampal area and a normal pyramidal neuron of CA1 highlighting the INs subtypes and the inhibition and disinhibition processes in healthy circuit. (B) Schematic representation of the hippocampal area and a degenerated pyramidal neuron of CA with amyloid plaques depositions and Tau tangles. In lower panel highlighting the INs subtypes and the dysregulation of hyperexcitability or hypoexcitability processes found in AD. Top panels of (A,B), created with BioRender.