HIPPOCAMPAL INTERNEURONS
AND THEIR ROLE IN CONTROLLING EXCITABILITY
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Chris
J. McBain, Ph.D., Principal Investigator Marco Atzori, Ph.D., Postdoctoral Fellow D. Ieuan Evans, Ph.D., Postdoctoral Fellow J. Joshua Lawrence, Ph.D., Postdoctoral Fellow Saobo Lei, Ph.D., Postdoctoral Fellow Andre Fisahn, Ph.D., Guest Researcher Emily Phillips-Tansey, M.S., Biologist Zachary Grinspan, HHMI Scholar Harrison Walker, HHMI Scholar Jürgen Wess, Ph.D., Collaborator, LBD, NIDDK |
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GABAergic
inhibitory interneurons constitute a population of hippocampal cells whose
high degree of anatomical and functional divergence make them suitable candidates
for controlling the activity of large populations of principal neurons.
GABAergic inhibitory interneurons play a major role in the synchronization
of neuronal activity; in addition, they are involved in the generation of
large-scale network oscillations. Thus, interneurons function as a clock
that dictates when principal cells fire during suprathreshold excitatory
drive. Interneurons receive strong excitatory glutamatergic innervation
via numerous anatomically distinct afferent projections, and recent work
has demonstrated that the molecular composition of both AMPA-preferring
classes of glutamate receptors expressed at interneuron synapses are often
distinct from those found at principal cell synapses. Furthermore, single
inhibitory interneurons can synthesize distinct AMPA receptors with defined
subunit composition and target them to synaptic domains innervated by different
afferent inputs. Using high-resolution whole-cell patch clamp recording
techniques in brain slices of hippocampus and the auditory and barrel cortex,
the Section on Cellular and Synaptic Physiology, directed by Chris McBain,
investigates differential mechanisms of synaptic transmission onto hippocampal
inhibitory interneurons and the role of intrinsic voltage-gated channels
in regulating interneuron excitability. Differential Synaptic Processing in the Auditory Cortex Atzori, Lei, Evans, McBain Sound features are blended together en route to the CNS before being discriminated for further processing by the cortical synaptic network. The mechanisms underlying this synaptic processing, however, are largely unexplored. We investigated intracortical processing of the auditory signal by simultaneous recording from pairs of connected principal neurons in layer II/III in slices from A1 auditory cortex in vitro. Physiological patterns of stimulation in the presynaptic cell revealed two populations of postsynaptic events that differed in mean amplitude, failure rate, kinetics, and short-term plasticity. We termed the events weak or stationary connections and strong and depressing connections. In contrast, transmissions between layer II/III pyramidal neurons in the barrel cortex were uniformly of large amplitude and high release probability (strong), suggesting that the division of labor observed between auditory cortical pyramidal neurons is unique and not common to layer II/III pyramidal neurons. We propose that these unique features of auditory cortical transmission provide two distinct mechanisms for discerning and separating transient from stationary features of the auditory signal at an early stage of cortical processing. Activation of Kinetically Distinct Synaptic Conductances on Interneurons by Electrotonically Overlapping Afferents Walker, Lawrence, McBain The ability of hippocampal inhibitory interneurons to detect synchronous principal neuron activity is determined by the rapid postsynaptic conductance change associated with synaptic input. Mossy fiber and CA3 collateral synapses activate GABAergic inhibitory interneurons to provide feedforward and feedback inhibitory control of the CA3 hippocampal network via synapses comprising different AMPA receptors. Specifically, mossy fibers make synapses consisting of calcium-permeable AMPA receptors while CA3 recurrent collateral synapses arise exclusively through calcium-impermeable AMPA receptors. Because these synapses occur over variable electrotonic distances, which distort somatically recorded synaptic currents, it was not known whether these afferent-specific synaptic conductances were associated with different time courses that would endow synapses with distinct temporal properties. By altering the driving force at the site of the synapse and using a novel voltage jump method, we have demonstrated that the lifetime of the excitatory synaptic conductance is briefer at mossy fiber synapses than at recurrent collateral synapses. Moreover, both synaptic conductances occupied a range of overlapping electrotonic locations, ruling out the possibility that each AMPA synapse is compartmentalized within the somatodendritic axis. Thus, distinct AMPA receptor-mediated synaptic conductances allow single interneurons to act as differential integrators in the temporal encoding of information provided by feedforward and feedback synaptic activity that is independent of dendritic location. Induction of Hippocampal Gamma Oscillations Requires Coupling of the M1-Muscarinic Receptor to Two Mixed Cation Currents Fisahn, McBain In transient assemblies of neurons, oscillatory network activity at gamma frequencies (about 20 to 80 Hz) is of major importance in cortical information processing. Whereas the underlying synaptic mechanisms of gamma oscillations have been studied in detail, the ionic currents involved at the cellular level remain to be elucidated. Our work has demonstrated that in vitro gamma oscillations are selectively induced by muscarinic activation of M1 receptors in hippocampal CA3 pyramidal neurons but are absent in M1 receptor-deficient mice. Mice deficient in M2, M3, M4, and M5 receptors continue to show robust gamma oscillatory activity. Previous studies have suggested that the M-current (IM) of hippocampal pyramidal neurons is modulated by the M1 muscarinic receptor and therefore may play a role in cholinergically induced gamma oscillations. However, M1 receptor activation in hippocampal area CA3 depolarizes pyramidal neurons not by an action on IM but rather by increasing the mixed Na+/K+ conductance Ih and the Ca2+-dependent nonspecific cation current Icat. The resulting depolarization and concomitant increase in firing frequency is sufficient to induce gamma oscillations. Our data provide new insight into the molecular basis of gamma oscillations by unequivocally establishing a novel role for muscarinic modulation of Ih and Icat in rhythmic network activity. |
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