Carbachol modulates cellular excitability and recurrent synaptic connections in pyramidal cell-fast spiking neuron circuits of mouse prefrontal cortex

PAFUNDO DE; LEWIS DA; GONZALEZ-BURGOS G

Washington, DC

Congreso; 41st annual meeting of the Society for Neuroscience; 2011

Society for Neuroscience

Synchronized oscillations at γ frequency (30-80 Hz) in neocortical networks may be essential for cognitive function. In current models, γ is generated by reciprocal excitation-inhibition loops between pyramidal cells (Py) and fast spiking interneurons (FS). Importantly, γ oscillations in vivo may require cholinergic modulation and acetylcholine receptor activation by carbachol is commonly used to induce γ oscillations in vitro. However, the mechanisms by which cholinergic modulation is involved in producing oscillations are poorly understood. We thus studied the effects of cholinergic modulation on neuronal excitability and Py-FS synaptic connections in the mouse prefrontal cortex. Carbachol (CCH, a cholinergic receptor agonist) increased the excitability of Py and FS neurons during γ wave stimulation (50 Hz sinusoidal current waves, plus depolarizing steps of varying amplitude). CCH (10 µM) reduced the minimal current necessary to induce firing (It) by 35% (Py) and 55% (FS). 10 µM Ipratropium, (Ip) a muscarinic antagonist, significantly reversed these effects. Moreover, CCH increased by 19% the slope of the firing frequency vs current (f-I) curve in Py cells, an effect reversed by Ip. In the presence of 10 μM gabazine (GABAA antagonist) or 10 μM CNQX + 50 μM AP5 (AMPA and NMDA antagonists), CCH had similar effects on the It and f-I curve in both Py and FS neurons. In FS to Py synaptically-connected pairs, repetitive firing of action potentials (APs) at γ frequency in the FS cells (60 stimuli at 40 Hz, baseline stimulation: 5 Hz) produced significant activity-dependent short-term depression of the unitary IPSCs (uIPSCs) evoked in postsynaptic Py (57% depression at uIPSC55-60). CCH decreased uIPSC1 strength by 40% and reduced short-term depression of uIPSC55-60 to 43%. Consistent with a presynaptically-mediated effect, CCH increased the uIPSC1 failure rate (200%), but did not significantly affect the failure rate of uIPSC55-60. Unitary EPSCs (uEPSCs) at Py to FS connections showed significant (67%) short-term depression of uEPSC25-30 during repetitive Py firing (30 APs evoked in the Py at 20 Hz, baseline stimulation: 2.5 Hz). CCH reduced uEPSC1 strength by 40% and decreased short-term depression of uEPSC25-30 to 32%. Moreover, CCH increased the uEPSC1 failure rate by 250% without changing failure rate for uEPSC25-30. Our data suggest that 1) increasing Py and FS excitability and 2) normalizing PSC amplitude throughout episodes of γ frequency firing (by decreasing short-term depression at the expense of decreasing uPSC strength) may play crucial roles in the mechanisms underlying induction of γ oscillations by cholinergic modulation in cortical circuits.