No abstract

Summary Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here we examine the function of the Tuberous Sclerosis Complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. We find that TSC/mTOR is a central component of a positive feedback loop that promotes network activity by repressing inhibitory synapses onto excitatory neurons. In Tsc1 KO neurons, weakened inhibition caused by deregulated mTOR alters the balance of excitatory and inhibitory synaptic transmission leading to hippocampal hyperexcitability. These findings identify the TSC/mTOR pathway as a novel regulator of neural network activity and have implications for the neurological dysfunction in disorders exhibiting deregulated mTOR signaling.

The basal ganglia (BG) are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning1. Current models postulate that the BG modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by the BG via direct (dSPNs) and indirect (iSPNs) pathway striatal projection neurons2–4. The BG thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems5. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the BG, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT+ cells, which have been historically identified as an extension of the nucleus basalis (NB), as well as ChAT− cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signaling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the BG to modulate frontal cortices.