Novel pharmacological targets for GABAergic dysfunction in ADHD

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopment disorder that affects approximately 5% of the population. The disorder is characterized by impulsivity, hyperactivity, and deficits in attention and cognition, although symptoms vary across patients due to the heterogenous and polygenic nature of the disorder. Stimulant medications are the standard of care treatment for ADHD patients, and their effectiveness has led to the dopaminergic hypothesis of ADHD in which deficits in dopaminergic signaling, especially in cortical brain regions, mechanistically underly ADHD pathophysiology. Despite their effectiveness in many individuals, almost one-third of patients do not respond to stimulant treatments and the long-term negative side effects of these medications remain unclear. Emerging clinical evidence is beginning to highlight an important role of dysregulated excitatory/inhibitory (E/I) balance in ADHD. These deficits in E/I balance are related to functional abnormalities in glutamate and Gamma-Aminobutyric Acid (GABA) signaling in the brain, with increasing emphasis placed on GABAergic interneurons driving specific aspects of ADHD pathophysiology. Recent genome-wide association studies (GWAS) have also highlighted how genes associated with GABA function are mutated in human populations with ADHD, resulting in the generation of several new genetic mouse models of ADHD. This review will discuss how GABAergic dysfunction underlies ADHD pathophysiology, and how specific receptors/proteins related to GABAergic interneuron dysfunction may be pharmacologically targeted to treat ADHD in subpopulations with specific comorbidities and symptom domains. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

Keywords: ADHD; Anterior cingulate cortex; Attention-deficit/hyperactivity disorder; Cortex; GABA; GPCR; Glutamate; Interneuron; Neurodevelopment; Prefrontal cortex; Psychiatry; Synaptic plasticity; Translational.

Figure 1:

Overview of ADHD pathophysiology related to GABAergic and cortical dysfunction. Reduced GABA concentrations in the cortex and striatum of ADHD have been reported using MRS (top box). Several genes identified in genome-wide association studies (GWAS) linked to GABAergic function are associated with ADHD (middle box). Altered GABA concentrations have been reported in the anterior cingulate cortex (ACC) and prefrontal cortex (PFC) during behavioral tasks related to ADHD symptoms of impulsivity and inattention (bottom box).

Figure 2:

GABAergic SST interneurons (blue) express Elfn1 (green) which physically recruits and anchors mGlu₇ (purple) into place at presynaptic terminals of excitatory pyramidal neurons (yellow). Elfn1 promotes strongly facilitating currents in postsynaptic SST interneurons and Elfn1/mGlu₇ interactions create a delayed feedback loop that prevents excessive excitation of pyramidal neurons. Loss of Elfn1 diminishes late strongly facilitating currents in SST interneurons (inset), leading to impaired GABAergic signaling and hyperexcitability of pyramidal neurons. It is speculated that the additional loss of presynaptic ionotropic kainate receptors (orange) may contribute to loss of late strongly facilitating currents, leading to overall net loss of excitation of SST interneurons. It is hypothesized that ADHD patients with Single Nucleotide Polymorphisms (SNPs) in ELFN1 and GRM7 have impaired GABAergic signaling in the cortex that are mediated through GABAergic interneuron dysfunction, leading to pyramidal neuron hyperexcitability and disruptions in excitatory/inhibitory (E/I) balance. Representative traces of excitatory postsynaptic currents (EPSCs) following 5 trains of stimulation in wild-type (black) and Elfn1 knockout mice (red, adapted from Stachniak et al., 2019 and Stachniak et al., 2023).