Inhibitory interneurons in brain functionn the harmonious brain, excitatory
and inhi-bitory synaptic signals coexist in
a purposeful balance.However, whereas the neurons that
transmit excitatorysignals often have rather stereotyped
properties, the cellsthat signal inhibition in the cortex
and hippocampus arehighly diverse and strikingly different. Inhibitory
cells—mostly interneurons because of their
often short-rangeeffect—signal to other neurons
by liberating, in mostcases, the neurotransmitter g-aminobutyric
acid (GABA).Most importantly, the interneurons
are built for speed:their action potential is traditionally
faster than that ofpyramidal cells. Furthermore, the
kinetics of synapticevents that excite inhibitory cells
are faster than thosethat excite pyramidal cells.1,2 The
functional result is thatpyramidal cell firing is under strict
time control to pre-vent run-away excitation (Figure
1). For instance, infeedforward inhibition, the bisynaptic inhibitoryresponse arrives only 1 to 5 milliseconds
after the mono-synaptic excitatory input and thereby
limits the timewindow for the summation of excitatory
inputs to gen-erate an action potential.3 In
addition to feedforwardinhibition, there is feedback
inhibition, the output-reg-ulated breaking system for pyramidal
cell firing.The fir-ing of a pyramidal cell activates
the inhibitory interneu-ron, which, in turn, inhibits
the pyramidal cell. Once thefeedback inhibition decays, the
principal cell is able tofire again and initiates another cycle
of inhibition.Thus,2 6 1B a s i c r e s e a r c hInhibitory interneurons in the brain
provide the balanceto excitatory signaling. On the basis
of brain imaging andhuman genetics, a deficit in GABAergic
inhibition (GABA,g-aminobutyric acid)
has been identified as contributingto the pathophysiology of anxiety
disorders, epilepsy, andschizophrenia. Therapeutically, GABAA receptors
play amajor role as targets for benzodiazepine
drugs. The ther-apeutic relevance of the multitude
of structurally diverseGABAA receptor
subtypes has only recently been identi-fied. a1-GABAA receptors
were found to mediate seda-tion, anterograde amnesia, and part
of the seizure pro-tection of these drugs, whereas a2-GABAA receptors,
butnot a3-GABAA receptors,
mediate anxiolysis. Rational drugtargeting to specific receptor subtypes
has now becomepossible. Only restricted neuronal
networks will be mod-ulated by the upcoming subtype-selective drugs. Forinstance, anxiolytics devoid of drowsiness
and sedationpromise more sophisticated interventions
in anxiety dis-orders. A new pharmacology of the
benzodiazepine siteis on the horizon.Dialogues Clin Neurosci.
2002;4:261-269.Pathophysiological aspects of diversity in neuronal inhibition:a new benzodiazepine pharmacologyHanns Möhler, PhDKeywords: GABA (g-aminobutyric acid); GABAAreceptor; neuronal inhibition; anxiety; epilepsy; schizophrenia;
benzodiazepineAuthor affiliations: Institute of Pharmacology and Toxicology, University ofZurich and Department of Applied Biosciences, Federal Institute of Technology (ETH)
Zurich, Zurich,
SwitzerlandAddress for correspondence: Prof
H. Möhler, Institute of
Pharmacology andToxicology, University of Zurich
and Department of Applied Biosciences,Federal Institute of Technology (ETH) Zurich, Winterthurerstr 190, CH-8057 Zurich, Switzerland(e-mail: mohler@pharma.unizh.ch)I
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