Tonic Modulation of GABA Release by Nicotinic Acetylcholine Receptors in Layer V of the Murine Prefrontal Cortex

Abstract

By regulating the neocortical excitability, nicotinic acetylcholine receptors (nAChRs) control vigilance and cognition and are implicated in epileptogenesis. Modulation of gamma-aminobutyric acid (GABA) release often accompanies these processes. We studied how nAChRs regulate GABAergic transmission in the murine neocortex with immunocytochemical and patch-clamp methods. The cholinergic fibers densely innervated the somatosensory, visual, motor, and prefrontal cortices (PFC). Laminar distribution was broadly homogeneous, especially in the PFC. The cholinergic terminals were often adjacent to the soma and dendrites of GABAergic interneurons, but well-differentiated synapses were rare. Tonically applied nicotine (1-100 microM) increased the frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) on pyramidal neurons in PFC layer V. The contribution of nAChR types was assessed by using 1 microM dihydro-beta-erythroidine (DHbetaE), to block heteromeric nAChRs, and 10 nM methyllycaconitine (MLA), to block homomeric nAChRs. Both inhibitors antagonized the effect of nicotine on IPSCs, suggesting that mixed nAChR types control pyramidal neuron inhibition in layer V. To determine whether nAChRs are expressed on basket cells' terminals, we studied miniature IPSCs (mIPSCs). These were revealed using 0.5 microM tetrodotoxin and 50 microM Cd(2+) to isolate the GABAergic terminals from the action potential drive. The nicotinic stimulation of mIPSCs was antagonized by DHbetaE, but not MLA, indicating that heteromeric nAChRs prevail in GABAergic terminals. Immunocytochemistry confirmed the expression of nAChRs on basket cells' somata and terminals. Finally, when the ionotropic glutamatergic transmission was blocked, nicotine partially inhibited the IPSCs, an effect counteracted by both DHbetaE and MLA. Therefore, a fraction of nAChRs are capable of activating GABAergic interneurons that in turn inhibit other GABAergic interneurons, thereby reducing the IPSCs. We conclude that heteromeric nAChRs control GABA release presynaptically, whereas mixed nAChRs regulate both excitation and inhibition of interneurons, the balance depending on the overall glutamatergic drive.

A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex

“…This finding suggests that nAChR activation rescues CMOR performance by enhancing GABAergic activity. In support of this, electrophysiological findings show that activation of nAChRs increases GABAergic currents in the cortex and hippocampus (Alkondon and Albuquerque, 2001;Couey et al, 2007;Aracri et al, 2010). Moreover, the GABAergic system is severely affected in schizophrenia patients because GABAergic markers such as parvalbumin (PV) are reduced in the hippocampus and prefrontal cortex (PFC) (Lewis et al, 2005;Lewis et al, 2012).…”

“…The use of this high-chloride intracellular solution in neurons held at Ϫ75 mV allows for the observation GABA A receptor activation via positive inward currents that result from chloride exiting the open ligand-gated ion channel (Couey et al, 2007;Bailey et al, 2010). All recordings were performed in layer 2/3 of the OFC, which was visualized by recording immediately dorsal to the apex of layer 1 in the OFC (Van De Werd and Uylings, 2008).…”

“…However, because of the structure of the CMOR task, it is impossible to assess multisensory integration abilities in the absence of mnemonic demand. To explore further the severe multisensory impairment in ketamine-treated rats, we have developed a novel multisensory oddity (MSO) task that is a variation on the perceptual oddity task previously used to study complex visual perception in rodents (Bartko et al, 2007). The MSO task permits assessment of multiple modality combinations (e.g., olfactory-visual) and multisensory integration independent of memory demand.…”

“…Pharmacological treatments targeting nicotinic acetylcholine receptors (nAChRs) have procognitive effects in schizophrenia patients (Smith et al, 2006;Barr et al, 2008;Lieberman et al, 2013). Accordingly, nicotine and specific nAChR agonists alleviate cognitive deficits in rodent models of schizophrenia Wildeboer and Stevens, 2008;Rushforth et al, 2011), including the CMOR impairment reported in ketamine-treated rats (Jacklin et al, 2012;Cloke and Winters, 2015).…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…In several mouse models of autism this lack of homeostasis of excitatory and inhibitory signaling was observed Gogolla et al, 2009). In the frontal cortex, cholinergic transmission can modulate cortical tone establishing a homeostasis of excitatory and inhibitory signals (Aracri et al, 2010). In layer V of the prefrontal cortex, nAChR activation increases the threshold for activating glutamatergic synapses (Couey et al, 2007), whereas GABA release is stimulated in several cortical layers by nAChR activation (Alkondon et al, 2000).…”