Cholinergic and GABAergic modulation of glutamatergic synaptic transmission in the hippocampus.

摘要

Behavioral data from rats and humans has shown that administering an acetylcholine (ACh) antagonist can block encoding of information. Administration during recall does not affect recall of previously encoded information. ACh therefore may be vital to the dynamics of encoding new memories either through direct action, or through the activation of GABAergic neurons. ACh modulation of transmission may act selectively to suppress internal processing by inhibiting the glutamatergic synapses of recurrent collateral fibers allowing incoming information to predominate during encoding, preventing interference between new and older information (Hasselmo, 1999).;The effects of the ACh agonist carbachol (CCh) were tested on excitatory post-synaptic potentials (EPSPs) in hippocampal slice preparations from rats. In region CA3, CCh suppressed EPSPs evoked at collateral synapses (n = 4) significantly more than perforant path projections (n = 9) at concentrations including 1 muM (31.7%, 15.2%, respectively; p = .034), 5 muM (70.1%, 41.0%; p = .012), and 20 muM (85.76%, 53.7%; p = .004).;Both the M1 and the M2 muscarinic subtypes have been suggested as the predominant receptor subtype responsible for this presynaptic inhibition of excitatory transmission by ACh. This debate has suffered from a lack of specific data, with particular subtype contributions inferred from effects of less selective agonists and antagonists. This issue is clarified here through experiments with mice having the M1 receptor gene knocked out. In hippocampal slices, muscarine caused significantly less suppression of EPSPs in m1 knockouts (n = 8) than in wild type controls (n = 9) at 5 muM (46.2%, 66.2%, respectively; p = .019) and 20 muM (46.2%, 66.2%; p = .007) concentrations. Further studies using selective agonists and antagonists are also presented.;Recent computational models suggest that these changes in dynamics could happen during cycles of theta rhythm, a 3--12 Hz oscillation of hippocampal EEG. However, ACh effects may not be sufficiently rapid to change within a theta cycle. GABA modulation of synaptic transmission via presynaptic GABAB receptors may have a sufficiently rapid time course. Pressure application of GABA to the recording site caused suppression of potentials with rising and decay time constants well under 1 second. Thus, the time constant of GABAergic modulation of transmission may allow significant changes in transmission during a single theta cycle.