The Role of PI3K-AKT-mTOR Signaling in Neurological Disorder Neurophysiology and Synaptic Plasticity

• Main Author: Kushner, John Keenan
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2024
• Subjects: Biochemistry; Medicine; Neurosciences; Psychology
• ISBN: 9798383702482

The PI3K-AKT-mTOR signaling pathway plays a crucial role in neocortical development and synaptic plasticity. Embryonic mutations along this pathway are implicated in neurological disorders, such as malformations of cortical development (MCDs), autism spectrum disorder, and psychiatric disorders. Understanding how this pathway alters neural activity, network synchronization, and synaptic plasticity is critical in order to develop more precise therapies. By performing electrophysiologic recordings on human epilepsy ex vivo brain slices, we demonstrate that hyperactivation of this pathway leads to changes in layer 2/3 (L2/3) pyramidal neuron intrinsic properties, including a reduction in voltage sag and neural firing rates and higher membrane decay, suggesting a homeostatic reduction in PN excitability, but perturbed Ih current, which could result in increased synaptic summation. Secondly, we characterized the influence of the pro-epileptic voltage-gated K+ channel blocker, 4-aminopyridine (4-AP), on L2/3 PN intrinsic properties and observed an increase in action potential halfwidth and reduced firing rate accommodation in human epileptic PNs. 4-AP also induced synchronized paroxysmal discharges in epileptic tissue and synchronized oscillations that were hyperpolarizing at physiologic membrane potentials. Additionally, we found that the hyperpolarizing oscillations (HypOs) were larger in mTOR-related epileptic tissue compared to control tissue and were not mediated by GABAergic neurotransmission or cation-chloride cotransporters, NKCC1 and KCC2. Instead, HypOs were dependent on network activity, partially mediated by gap junctions, and were eliminated by activation of Kv7.2-7.5 (KCNQ) channels. We propose that HypOs are due to GABAergic synchronization that induces local microcircuit [K+]o fluctuations without need for neurotransmission and that PI3K-AKT-mTOR pathway activation leads to circuit hyper synchronization. Contrarily, we found that reducing this pathways activation via Akt1 KO in mice lead to reduced cannabinoid 1 receptor (CB1R) expression at GABAergic terminals in an age-dependent manner resulting in reduced endocannabinoid-mediated suppression of inhibition in young adult (P30) mice. Therefore, our data indicate that hyperactivation of the PI3K-AKT-mTOR pathway leads to hyperactive cortical circuits and changes in neural excitability to foster epileptiform activity while reducing the activation of this pathway promotes less eCB-mediated plasticity at GABAergic synapses and enhanced GABAergic neurotransmission, and this correlates to long-term behavioral consequences related to psychiatric disorders.