Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

https://science.sciencemag.org/content/sci/233/4761/305.full.pdf

Studies and perspectives of protein kinase C

A model of the neuropsychology of anxiety is proposed. The model is based in the first instance upon an analysis of the behavioural effects of the antianxiety drugs (benzodiazepines, barbiturates, and alcohol) in animals. From such psychopharmacologi-cal experiments the concept of a “behavioural inhibition system” (BIS) has been developed. This system responds to novel stimuli or to those associated with punishment or nonreward by inhibiting ongoing behaviour and increasing arousal and attention to the environment. It is activity in the BIS that constitutes anxiety and that is reduced by antianxiety drugs. The effects of the antianxiety drugs in the brain also suggest hypotheses concerning the neural substrate of anxiety. Although the benzodiazepines and barbiturates facilitate the effects of γ-aminobutyrate, this is insufficient to explain their highly specific behavioural effects. Because of similarities between the behavioural effects of certain lesions and those of the antianxiety drugs, it is proposed that these drugs reduce anxiety by impairing the functioning of a widespread neural system including the septo-hippocampal system (SHS), the Papez circuit, the prefrontal cortex, and ascending monoaminergic and cholinergic pathways which innervate these forebrain structures. Analysis of the functions of this system (based on anatomical, physiological, and behavioural data) suggests that it acts as a comparator: it compares predicted to actual sensory events and activates the outputs of the BIS when there is a mismatch or when the predicted event is aversive. Suggestions are made as to the functions of particular pathways within this overall brain system. The resulting theory is applied to the symptoms and treatment of anxiety in man, its relations to depression, and the personality of individuals who are susceptible to anxiety or depression.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0140525X00013066

Précis of The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System..

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

/pdf/short-term-synaptic-plasticity-5d4dx79319.pdf

Short-Term Synaptic Plasticity

Interneurons of the hippocampus

Introduction to synaptic circuits, Gordon M.Shepherd and Christof Koch membrane properties and neurotransmitter actions, David A.McCormick peripheral ganglia, Paul R.Adams and Christof Koch spinal cord - ventral horn, Robert E.Burke olfactory bulb, Gordon M.Shepherd, and Charles A.Greer retina, Peter Sterling cerebellum, Rodolfo R.Llinas and Kerry D.Walton thalamus, S.Murray Sherman and Christof Koch basal ganglia, Charles J.Wilson olfactory cortex, Lewis B.Haberly hippocampus, Thomas H.Brown and Anthony M.Zador neocortex, Rodney J.Douglas and Kevan A.C.Martin Gordon M.Shepherd. Appendix: Dendretic electrotonus and synaptic integration.

The synaptic organization of the brain

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids.

1. Intracellular recordings from CA1 pyramidal cells in the rat hippocampal slice preparation have been used to study the neuronal pathways involved in hippocampal synaptic inhibition.

2. When direct comparisons are made in a single pyramidal cell, orthodromic stimulation delivered to stratum (s.) radiatum in normal recording conditions is found to be more effective than antidromic stimulation in producing inhibitory post-synaptic potentials (i.p.s.p.s).

3. Orthodromic i.p.s.p.s in normal conditions appear to be complex, multiphasic events, whereas antidromic i.p.s.p.s are relatively simple. The orthodromic i.p.s.p. involves both a GABA-mediated dendritic component and a non-GABA-mediated component neither of which is activated by antidromic stimulation.

4. Barbiturates induce a late depolarizing phase of the orthodromic response, a `depolarizing i.p.s.p.', which is mediated by GABA. The depolarizing i.p.s.p. is not produced by antidromic stimulation.

5. Injections of tetrodotoxin and bicuculline methiodide localized to either somatic or apical dendritic regions reveal that the depolarizing i.p.s.p. is produced by GABA released from neuronal elements in the dendritic field which acts on pyramidal cell dendrites.

6. The depolarizing i.p.s.p. is strongly temperature-dependent and increases in amplitude and duration progressively as slices are cooled from 37 to 22 °C.

7. Depolarizing i.p.s.p.s can be produced by orthodromic stimulation in s. oriens as well as in s. radiatum. In each case the depolarizing i.p.s.p.s appear localized to the dendrites in the field stimulated.

8. We conclude that the depolarizing i.p.s.p. evident in the presence of barbiturates is caused by the same synaptic release of GABA which in normal conditions produces hyperpolarizing dendritic i.p.s.p.s.

9. Numerous comparisons between orthodromic and antidromic stimulation indicate that dendritic i.p.s.p.s are activated by feed-forward pathways.

Feed-forward dendritic inhibition in rat hippocampal pyramidal cells studied in vitro.

1. The rat hippocampal slice preparation has been used in conjunction with intracellular recording and ionophoresis to study the action of gamma-aminobutyric acid (GABA) on CA1 pyramidal cells.2. GABA elicits a hyperpolarizing (h.) response at the soma. The reversal potential of this h. response is the same as for inhibitory post-synaptic potentials (i.p.s.p.s) evoked by stimulating pyramidal cell axons.3. GABA elicits primarily depolarizing (d.) responses when applied to the apical dendrites, but h. responses can also be found.4. The GABA antagonists bicuculline methiodide, picrotoxin, penicillin, and pentylenetetrazole are all ten to one hundred times more potent on the d. response than on the h. response. Hyperpolarizing responses are uncovered in the dendrites when intermediate doses of these drugs block the d. response.5. The GABA analogue, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP), which has been proposed to activate synaptic receptors preferentially in other systems, elicits h. responses in the dendrites. It is one seventh as potent as GABA in eliciting d. responses.6. Pentobarbitone enhances d. responses to a much greater extent than h. responses, while diazepam enhances h. responses to a greater extent.7. Nipecotic acid, low temperature, and low sodium media all increase the size of d. responses to ionophoretically applied GABA indicating that an active uptake process limits their size.8. We conclude that h. responses reflect the activation of synaptic receptors which are highly concentrated on the pyramidal cell soma-initial segment, but are also present on the dendrites. Depolarizing responses, which are evoked in the dendrites, reflect the activation of extrasynaptic receptors.9. We propose that an ordinarily undetectable amount of synaptically released GABA can ;spill' over onto extrasynaptic (d.) receptors. Depolarizing receptor activation can be detected in the presence of pentobarbitone. Spillover is markedly enhanced at subphysiological temperatures presumably due to enhanced release of GABA and impairment of the GABA uptake system.

Pharmacological evidence for two kinds of GABA receptors on rat hippocampal pyramidal cells studied in vitro

Neuronal activity in dorsal hippocampus was recorded in rabbits-during classical conditioning of nictitating membrane response, with tone as conditioned stimulus and corneal air puff as unconditioned stimulus. Unit activity in hippocampus rapidly forms a temporal neuronal "model" of the behavioral response early in training. This hippocampal response does not develop in control animals given unpaired stimuli.

https://science.sciencemag.org/content/sci/192/4238/483.full.pdf

Neuronal substrate of classical conditioning in the hippocampus.

Using intracellular recording techniques in CA1 cells in the hippocampal slice, we studied the responses of cells to synaptically released and iontophoretically applied GABA. With high-resistance, Cl(- )-filled electrodes, which inverted and enlarged the responses at normal resting potentials, we examined spontaneous GABA-mediated IPSPs. Usually we recorded the spontaneous events in the presence of carbachol (10–25 microM), which significantly increased IPSP frequency and blocked potentially confounding K+ conductances. Following a train of action potentials, spontaneous IPSPs were transiently suppressed. This suppression could not be accounted for by membrane conductance changes following the train or activation of a recurrent circuit. Whole-cell voltage-clamp recordings in the slice indicated that the amplitudes of the spontaneous GABAA inhibitory postsynaptic currents (IPSCs) were also diminished following the action potential train. In some cases BAY K 8644, a Ca2+ channel agonist, enhanced the suppression of IPSPs, while buffering changes in [Ca2+]i with EGTA or BAPTA prevented it. The monosynaptically evoked IPSC in the presence of 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX) and dl-2-amino-5-phosphonovaleric acid (APN) was also diminished following a train of action potentials; however, iontophoretically applied GABA responses did not change significantly. These studies suggest that localized physiological changes in postsynaptic [Ca2+]i potently modulate synaptic GABAA inputs and that this modulation may be an important regulatory mechanism in mammalian brain.

https://www.jneurosci.org/content/jneuro/12/10/4122.full.pdf

Bradley E. Alger

Papers

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids.

Feed-forward dendritic inhibition in rat hippocampal pyramidal cells studied in vitro.

Pharmacological evidence for two kinds of GABA receptors on rat hippocampal pyramidal cells studied in vitro

Neuronal substrate of classical conditioning in the hippocampus.

Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells