Regulation of glutamate release by heteromeric nicotinic receptors in layer V of the secondary motor region (Fr2) in the dorsomedial shoulder of prefrontal cortex in mouse

Abstract

We studied how nicotinic acetylcholine receptors (nAChRs) regulate glutamate release in the secondary motor area (Fr2) of the dorsomedial murine prefrontal cortex, in the presence of steady agonist levels. Fr2 mediates response to behavioral situations that require immediate attention and is a candidate for generating seizures in the frontal epilepsies caused by mutant nAChRs. Morphological analysis showed a peculiar chemoarchitecture and laminar distribution of pyramidal cells and interneurons. Tonic application of 5 mM nicotine on Layer V pyramidal neurons strongly increased the frequency of spontaneous glutamatergic excitatory postsynaptic currents. The effect was inhibited by 1 mM dihydro-b-erythroidine (which blocks a4-containing nAChRs) but not by 10 nM methyllicaconitine (which blocks a7-containing receptors). Excitatory postsynaptic currents s were also stimulated by 5-iodo-3-[2(S)-azetidinylmethoxy]pyridine, selective for b2-containing receptors, in a dihydro-b-erythroidine -sensitive way. We next studied the association of a4 with different populations of glutamatergic terminals, by using as markers the vesicular glutamate transporter type (VGLUT) 1 for corticocortical synapses and VGLUT2 for thalamocortical projecting fibers. Immunoblots showed higher expression of a4 in Fr2, as compared with the somatosensory cortex. Immunofluorescence showed intense VGLUT1 staining throughout the cortical layers, whereas VGLUT2 immunoreactivity displayed a more distinct laminar distribution. In Layer V, colocalization of a4 nAChR subunit with both VGLUT1 and VGLUT2 was considerably stronger in Fr2 than in somatosensory cortex. Thus, in Fr2, a4b2 nAChRs are expressed in both intrinsic and extrinsic glutamatergic terminals and give a major contribution to control glutamate release in Layer V, in the presence of tonic agonist levels. Synapse 67:338-357, 2013. V C 2013 Wiley Periodicals, Inc.

Multi-electrode array study of neuronal cultures expressing nicotinic β2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy

“…Determining the ADNFLE mechanisms is not straightforward because, in the frontal cortex, heteromeric nAChRs regulate both glutamate and GABA release (Gioanni et al, 1999; Alkondon et al, 2000; Lambe et al, 2003; Couey et al, 2007; Dickinson et al, 2008; Aracri et al, 2010, 2013; Marchi and Grilli, 2010). The well-known sensitivity of neuronal excitability to the GABAergic tone has led to hypotesize that an altered nAChR-dependent modulation of the GABAergic system may facilitate seizures.…”

Pathologic role of neuronal nicotinic acetylcholine receptors in epileptic disorders: implication for pharmacological interventions

“…A recent study also demonstrated that tonic application of nicotine on layer V of the secondary motor region in the dorsomedial shoulder of mice prefrontal cortex strongly increased the frequency of spontaneous glutamatergic excitatory post-synaptic currents (Aracri et al, 2013). They also found that α 4 β 2 nAChRs are expressed in both intrinsic and extrinsic glutamatergic terminals and give a major contribution to control glutamate release in layer V, in the presence of tonic agonist levels (Aracri et al, 2013). Nicotine also modulates the release of other neurotransmitters such as dopamine, GABA, acetylcholine, and noradrenaline regulated by multiple subtypes (Gotti et al, 2006b).…”

“…This effect was abolished in mice lacking the β 2 nAChR subunit, suggesting that prefrontal α 4 β 2 nAChRs are involved in glutamate release (Lambe et al, 2003;Parikh et al, 2010). A recent study also demonstrated that tonic application of nicotine on layer V of the secondary motor region in the dorsomedial shoulder of mice prefrontal cortex strongly increased the frequency of spontaneous glutamatergic excitatory post-synaptic currents (Aracri et al, 2013). They also found that α 4 β 2 nAChRs are expressed in both intrinsic and extrinsic glutamatergic terminals and give a major contribution to control glutamate release in layer V, in the presence of tonic agonist levels (Aracri et al, 2013).…”

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

“…Although such investigations only provide indirect measures and not unequivocal proofs, a number of studies have indicated that both stoichiometries are expressed in vivo, suggesting that the existence of two stoichiometries is not just an experimental in vitro phenomenon. Both LS and HS receptors have been proposed to mediate glutamate release in mPFC ( [51] and [52], respectively), whereas only HS receptors so far have been suggested to mediate dopamine release in striatum [42,53]. Both stoichiometries may contribute to neurotransmission in Renshaw cells in mouse spinal cord [54].…”