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The Journal of Neuroscience, December 1995, 15(12): 7916-7928 Transiently Selective Activation of Phosphoinositide Turnover in Layer V Pyramidal Neurons After Specific mGluRs Stimulation in Rat Somatosensory Cortex During Early Postnatal Development J. A. Bevilacqua,’ C. Peter Dowries,* and Pedro R. Lowensteinl ‘Laboratory of Cellular and Molecular Neurobiology, Physiology Unit, School of Molecular and Medical Biosciences, University of Wales College of Cardiff, Cardiff CFl 3US and 2Department of Biochemistry, University of Dundee, Dundee DDl 4HN, United Kingdom Biochemical analysis of muscarinic- and metabotropic-glu- that the neocortex displays a higher susceptibility to experience- tamate receptor stimulated phosphoinositide (PI) turnover induced synaptic modification during early stages of postnatal in rat cortical preparations during the first three weeks of development (Hubel and Wiesel, 1970; Van der Loos and Wool- postnatal development indicates the existence of a tran- sey, 1973; Blakemore and Van Sluyters, 1974; Woolsey and siently increased accumulation of labeled inositol poly- Wann, 1976; Cynader and Mitchell, 1980; Fox, 1992; Schlaggar phosphates during the first postnatal week (Gonzales and et al., 1993; Fox and Zahs, 1994). Studies in the rat somatosen- Crews, 1985; Dudek et al., 1989). We now report for first sory cortex have shown the existence of a narrow period during time the visualization of those neurons responding with in- early postnatal development during which the anatomical and creased PI turnover to glutamatergic or cholinergic-recep- functional structure of the neocortex is highly modifiable in re- tor stimulation in rat somatosensory cortex during early sponse to changes in the afferent input from the peripheral sen- postnatal development utilizing a recently described meth- sory organs, and after which the cortical circuitry remains rel- od (Bevilacqua et al, 1994). Three, 7, 10, 14, and 21 d old atively unchanged in response to modifications in afferent input rats were studied. Carbachol in the presence of lithium (Hubel and Wiesel, 1970; Blakemore and Van Sluyters, 1974; stimulates 3H-CMP-PA accumulation throughout the cortex Cynader and Mitchell, 1980). This particular period of postnatal at all ages studied. In comparison labeled neurons re- cortical development in mammals is known as the “critical” or sponding to t-ACPD in the presence of lithium were located “sensitive” period of neocortical development (Hubel and Wie- exclusively in layer V at P3 and P7, but were found labeled sel, 1970; Fox, 1992; Fox and Zahs, 1994) and has also been throughout the cortex at PlO. exhaustively documented in the cat and primate visual cortex Given that glutamate and cholinergic agonist stimulation (Hubel and Wiesel, 1970; Blakemore and Van Sluyters, 1974; are both necessary but not sufficient for cortical plasticity Cynader and Mitchell, 1980; Le Vay et al., 1980; Daw et al., to occur, and that muscarinic and mGluRs stimulation both 1992). Studies of the pathways involved in the regulation of this induce a peak in PI turnover response during the same pe- riod of experience-dependent neocortical plasticity, PI de- phenomenon indicate that three neurotransmitter systems are rived second messengers signals might be involved in the necessary for neocortical synaptic plasticity to proceed, namely: regulation of the molecular mechanisms of neuronal plas- glutamate (Shaw et al., 1984; Kleinschmidt et al., 1987), ACh ticity. Furthermore, our results show the anatomical cor- and noradrenaline (Bear and Singer, 1986). relate of receptor-specific PI turnover activation, and indi- In rat visual cortex, it has been shown that the critical period cate that specific agonist induced PI responses are age, for dark rearing and monocular deprivation induced changes of and layer specific. visual cortical function, occurs between days 2 140 of postnatal [Key words: phosphoinositide turnover, rat somatosen- life (Fagiolini et al., 1994). The peak in glutamate induced PI- sory cortex, development, critical period, autoradiography, turnover in rat cortex peaks at 1 week postnatal, and disappears metabotropic glutamate receptor] around 35-40 d postnatal. Very recently the correlation of the critical period of cortical modifiability in response to external Much work has been devoted to the phenomenological under- factors, and inducibility of long term potentiation (LTP) has been standing of the processes that lead to the establishment of the compared in the somatosensory and visual cortex. In somato- neocortical structure (Rauschecker, 1991). It is well documented sensory cortex LTP can be induced between days 3-7 postnatal, while in visual cortex it can be induced between days 14-21 Received Feb. 14, 1995; revised June 14, 1995; accepted July 17, 1995. (Crair and Malenka, 1995; Kirkwood et al., 1995). Thus, LTP We thank Mr. Bob Jones and Mr Guy Pitt, Photography Unit, School of Molecular and Medical Biosciences, U.W.C. C., for expert photographic assis- can be induced earlier in the somatosensory cortex, compared tance. We also acknowledge Dr. Jim Ralphs and Mr. Tony Hayes from Anatomy to the visual cortex. Unit, School of Molecular and Medical Biosciences, U.W.C.C., for the use of Receptors for noradrenaline (Levitt and Moore, 1979; Morris image analysis system equipment and useful technical advice. P.R.L. is a Re- search Fellow of The Lister Institute of Preventive Medicine. This work was et al., 1980), ACh (CortCs and Palacios, 1986; Spencer et al., supported by a Project Grant from The Wellcome Trust to C.P.D. and P.R.L. 1986; Buckley et al., 1988; Levey et al., 1991), and glutamate Correspondence should be addressed to Pedro R. Lowenstein, Molecular (Stephens et al., 1991; Abe et al., 1992; Shigemoto et al., 1992, Medicine Unit, Department of Medicine, University of Manchester, School of Medicine, Stopford Building, Oxford Road, Manchester Ml3 9PT, UK. 1993) are present in the developing rat neocortex, and the ex- Copyright 0 1995 Society for Neuroscience 0270-6474/95/1579 I6- I3$05.00/0 pression of some of these receptors has been recently demon- The Journal of Neuroscience, December 1995, 15(12) 7917 A Agonist A Agonist B B Agonist A Agonist B VI WM PO P3 PI PlO P14 P21 Adult rat age Figure 1. Schematic representation of the hypothetical anatomical substrates that could account for the neurotransmitter-induced peak in phos- phoinositide detected biochemically during the development of neocortex. A, Different neurotransmitters induce labeling throughout all cortical layers. The peak of neocortical PI turnover results from the stimulation of neurons in all cortical layers by several neurotransmitters. B, Distinct agonists induce layer specific labeling. The peak of neocortical PI turnover results from the stimulation of neurons in different cortical layers by individual neurotransmitters. C, Schematic representation of the PI turnover peak detected biochemically by measuring incorporation of 3H-inositol into inositol polyphosphates after specific receptor stimulation. Roman numerals indicate cortical layers; WA4, white matter; A, labeled neurons; the diagonal strip pattern represents neuropil labeling. strated to be transient (Blue and Johnston, 1994). In addition (Dudek and Bear, 1989; Bear and Dudek, 1991). If a certain noradrenaline, ACh and glutamate receptor stimulation increase threshold of neurotransmitter induced phosphoinositide turnover PI-turnover in rat cortex preparations (Berridge et al., 1982; is necessary for neocortical maturation to proceed, two mecha- Gonzales and Crews, 1985; Nicoletti et al., 1986a,b; Balduini et nisms could account for this transient peak (Fig. I),: either dif- al., 1991). Moreover, it has been shown that muscarinic and ferent neurotransmitters stimulate all layers simultaneously (Fig. glutamatergic agonist stimulated PI-turnover is higher in neonate 1A); or neurotransmitter stimulation is layer specific (Fig. 1B). than in adult cortex (Dudek et al., 1989). Interestingly, a similar Notice that both mechanisms could subserve a transient peak peak in PI response can be elicited in kitten neocortex by mus- (Fig. 1C). Alternatively, a mixed mechanism could also occur. carinic and mGluRs stimulation, and this transient peak parallels However, the exact mechanisms by which activation of PI the time window of the critical period of kitten visual cortex turnover via these neurotransmitter systems is affecting synaptic plasticity (Dudek and Bear, 1989). Therefore, it has been sug- plasticity is not completely clarified. While it has been suggested gested that increased PI-turnover is directly implicated in the that excitatory amino acid (EAA) receptor stimulation controls cellular mechanism that leads to neuronal neocortical plasticity the magnitude of synaptic plasticity changes occurring in the 7918 Bevilacqua et al. - Layer Specific Activation of PI Turnover in Neocortex neocortex, the catecholaminergic and noradrenergic systems ap- (pH 7.4) further 30 min. Afterwards, slices were dehydrated in increas- pear to play a permissive role over EAA effects (Bear and Du- ing concentrations of ethanol with a final step in propylene oxide. In- filtration in Durcupan resin was performed overnight. The next day, dek, 1991). Nevertheless, there has been no information so far slices were flat-embedded on glass slides in fresh Durcupan resin and regarding which individual neurons or cortical layers respond left to polymerized at 56°C during 48 hr. The coverslips were then with increased phosphoinositide
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