Regulation Of GABAergic Circuits In The Mouse Prefrontal Cortex And The Thalamic Reticular Nucleus

The y-aminobutyric acid (GABA)-ergic circuits play an important role in the mouse central nervous system. Parvalbumin (PV) positive fast-spiking (FS) neurons account for40-50%of all GABAergic interneurons in the neocortex. These neurons form several microcircuits in the PFC: first, they are connected with pyramidal neurons or other types of inteneurons through chemical synapses; second, they are interconnected via chemical and electrical synapses (FS-FS). In addition, subcortical PV neurons also receive synaptic input from cholinergic neurons. All these projections are involved in many higher cognitive functions by regulating the GABAergic circuit in the central nervous system.The prefrontal cortex (PFC) is responsible for higher cognitive functions such as decision, learning and working memory. The GABA circuit is regulated by many factors. Among them are neurotrophins like BDNF and FGF. Neuregulin1(NRG1), a member of the growth factor family, functions mainly through binding with the tyrosine kinase-type receptor ErbB4in the central nervous system. Both nrgl and erbb4are susceptibility genes for schizophrenia, yet their precise roles in schizophrenia are largely unknown. Reduced synchronization in several cortical regions, especially in the PFC, is associated with the core symptoms of schizophrenia. Recent studies show that NRG1may affect the hippocampal oscillations through ErbB4expressed on FS interneurons. However, the role of NRG1/ErbB4signaling in the synchronization of neurons in the PFC is unclear.The thalamic reticular nucleus (TRN) is located between the thalamus and the cortex and composed entirely of GABAergic neurons, of which most are PV neurons. TRN mainly receives cholinergic projections from the brainstem which has an important role in sleep regulation. A few morphologic studies suggested that TRN maybe receive fibers from cholinergic neurons of the nucleus basalis of Meynert (nbM). However, direct evidence linking the nbM cholinergic neurons to TRN PV interneurons is lacking, and the function of this circuit is unknown.Here, with the use of multiple approaches including electrophysiology, immunohistochemistry, optogenetics, we demonstrate that in the mouse PFC, NRG1enhanced the synchrony of the two major kinds of neurons through inhibitory synapses in the local network and increased the power of kainate-induced gamma oscillations in vivo. Furthermore, this effect was mediated by ErbB4receptors. While in the TRN, optical activation of nbM cholinergic neurons provided direct excitatory and inhibitory synaptic transmission to PV neurons via α7nicotinic acetylcholine receptors (α7nAChRs) and M1muscarinic acetylcholine receptors (Ml mAChRs), respectively. And the excitatory cholinergic transmission could regulate glutamatergic synaptic plasticity in these neurons. Both the excitatory transmission and the plasticity could be disrupted by Aβ exposure. Moreover, this functional cholinergic transmission from the nbM to the TRN was involved in memory consolidation. Therefore, abnormality of the neural GABAergic circuits may be related to the pathology of many higher cognitive disorders and likely causes many kinds of neuropsychiatric diseases such as schizophrenia.