1 Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK and , 2 Department of Physiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto 602-8566, Japan
Address correspondence to Zoltán Molnár, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK. Email: zoltan.molnar{at}anat.ox.ac.uk.
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Abstract |
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Introduction |
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How Do Thalamic Projections Cross Subdivisions Marked by Gene Expression Boundaries to Reach the Cortex?
In rodent, during the second and third week of gestation the forebrain is undergoing spectacular changes. During this period the embryonic forebrain will differentiate into distinct domains, termed prosomeres, each with specific morphological features and gene expression patterns (Puelles and Rubenstein, 1993). This is the period, in mice E1316, when thalamocortical and corticofugal axons have to travel through numerous rapidly forming subdivisions and boundaries of the embryonic brain. These critical boundaries outlined by distinct molecular properties (Puelles et al., 2000
), include the diencephalic telencephalic and the pallialsubpallial (PSPB) or striatocortical boundaries.
Both thalamocortical and corticofugal projections show puzzling behavior at these boundaries during their growth. The developing thalamocortical axons first proceed ventrally from the dorsal thalamus and then turn dorsolaterally at the diencephalictelencephalic junction, where they enter the internal capsule. They rapidly advance amongst a largely transient population of cells in this region (Métin and Godement, 1996), but then pause before traversing the corticostriatal junction. The earliest corticofugal projections, most of which originate from preplate neurons also pause at this boundary around E13/14 in mouse. Although projections from different cortical regions arrive at this zone at slightly different times, the front of the early corticofugal projection lines up along the striatocortical junction. Subsequent to their interaction with the striatocortical junction, the thalamocortical and corticothalamic fibers resume their advance, intimately associated with each other, and proceed towards their targets (Fig. 1A
).
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Early-generated, largely transient neuronal populations are known to extend pioneering axonal projections through these critical boundaries. It was proposed that these cells provide scaffolds or temporary targets, guide-post cells, for the developing axonal projections (McConnell et al., 1989; Mitrofanis and Guillery, 1993
). It has been suggested that the early outgrowth of thalamocortical axons from the diencephalon might be governed by pioneering projections from internal capsule cells (Métin and Godement, 1996
), while the crossing of the PSPB might be dependent on selective fasciculation with corticofugal projections (Molnár and Blakemore, 1995
). It has been postulated in the handshake hypothesis that axons from the thalamus and from the early-born cortical preplate cells meet and intermingle in the basal telencephalon, so that thalamic axons grow over the scaffold of preplate axons and become captured for the waiting period in the subplate (Blakemore and Molnár, 1990
). However, it still has not been unequivocally demonstrated whether selective fasciculation of the two fiber sets is essential for their crossing of this boundary. It is even less clear whether the order in which the thalamocortical and corticofugal projections interact holds any importance. We believe that the detailed examination of thalamocortical development and these critical forebrain regions in normal and various mutant mice shall help to resolve these questions.
Possible Role of Early Functional Interactions in Thalamocortical Self-organization
The first post-mitotic neurons of the cortex form the preplate. The preplate is subsequently split into a superficial marginal zone and a deep layer called subplate. The cortical plate then forms between these two layers, as neurons migrate from the ventricular and subventricular zones, passing through the intermediate zone and the subplate en route. Migration into the cortical plate occurs in an inside-out order (Rakic, 1977). The thalamic projections arrive to the cortex through the intermediate zone, which lies between the first-generated cells of the subplate layer and the subventricular zone. Upon thalamic fiber arrival, only an immature cortical plate, non-permissive for thalamic ingrowth is present, and therefore the thalamic fibers accumulate in the subplate before the cortex gradually becomes mature enough (Lund and Mustari, 1977
; Rakic, 1977
; Shatz and Luskin, 1986
).
It has been proposed that while the thalamic axons accumulate in the subplate they engage in activity-dependent interaction with these cells and this might lead to their realignment before they enter the cortex (Catalano and Shatz, 1998; Krug et al., 1998
). Thalamic axons are known to develop numerous transient side branches (Naegele et al., 1988
; Ghosh and Shatz, 1992
; Catalano et al., 1996
) as they accumulate in the subplate. The side branch formation might be regulated by electric fields of the activity patterns along the axons. Catalano and Shatz (Catalano and Shatz, 1998
) delivered TTX (sodium channel blocker) into the putative visual cortex of cat fetuses, at the time thalamic projections were arriving to the subplate. Lateral Geniculate Nucleus developed projections to cortical areas that they normally bypass and failed to enter the visual cortex. The few fibers that did enter had an aberrant topography within the cortical plate. Although this experiment suggests that even the initial phases of thalamocortical targeting might depend on early activation patterns, the exact nature of the required neural activity is not known. We set out to investigate the pattern of cortical activation after direct thalamic stimulation during the period of thalamic fiber accumulation using an optical recording technique. There are various forms of neurotransmitter release, which could activate recipient cells (Rizo and Südhof, 2002
). The Snap25 KO mouse (Washbourne et al., 2002
), where the action potential-regulated synaptic vesicle release is disrupted, provides an excellent model system to evaluate the contribution of regulated and spontaneous neurotransmitter release in embryonic cortical development.
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Overview of Methods |
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For the optical recording, we used 400 mm thick cut slices from embryonic (E17E21) and postnatal (P0P10) rat brains (Agmon et al., 1993). These were stained with a voltage-sensitive dye (RH482) and images were captured in a Fuji Deltaron 1700 differential image acquisition system after selective thalamic stimulation (Higashi et al., 2002
).
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Results |
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Emx2 KO
Emx2 is a member of the empty spiracles family of genes, and its expression in the anterior CNS of the developing mouse embryo follows a rostro-caudal gradient (Simeone et al., 1992; Gulisano et al., 1996
; Bishop et al., 2000
; Mallamaci et al., 2000
) (Fig. 1A
). Emx2 homozygous mutant mice die perinatally. Previous studies have shown that the lack of Emx2 results in some forebrain structural abnormalities. The most striking abnormalities are the severe reduction of cortical hemisphere size and the disruption in cortical lamination (Yoshida et al., 1997
; Mallamaci et al., 2000
). Lamination defects have been reported to occur in the neocortex of Emx2 KO mice, but the diencephalon develops relatively normally (Suda et al., 2001
). A disproportional, but orderly, arealization of the Emx2 mutant neocortex reflected by an expansion of rostral areas and a contraction of caudal areas has been described (Bishop et al., 2000
; Mallamaci et al., 2000
). This shift in areal identity in the cerebral cortex of Emx2 KO is matched by the altered distribution of thalamocortical projections. In order to understand how the altered thalamocortical axons occur in the Emx2 KO mice, we specifically tested the idea of whether thalamocortical axons become misrouted close to the start of their path towards the cortex, where cues other than the ones intrinsic to the cortex could influence their behavior. The tracing studies demonstrated that in Emx2 KO mice a large proportion of early thalamocortical projections were misrouted at the ventral border between the diencephalon and telencephalon. This abnormality occurred in conjunction with displaced connectivity of the internal capsule cells at the diencephalictelencephalic junction. Interestingly, most of the aberrant thalamic projections compensated for the ventral entry to the telencephalon and still ascended to the cortex, but their arrival was slightly delayed (López-Bendito et al., 2002
) (Fig. 1B
).
Pax6/LacZ KO
Pax6 has been found to have an essential role in brain morphogenesis (Walter and Gruss, 1991; Caric et al., 1997
; Stoykova et al., 1997
; Warren et al., 1999
), and has been implicated in early axonal pathfinding (Mastick et al., 1997
; Kawano et al., 1999
; Pratt et al., 2000
). A Pax6 positive group of cells was observed to extend along the PSPB, from the ventricular/subventricular zones towards the mantle of the basal telencephalon (Stoykova et al., 1997
; Smith-Fernandez et al., 1998
; Puelles et al., 2000
) (Fig. 1A
). Loss of Pax6 function in the Pax6Sey/Sey mutant brains, results in a prominent ventralization of the molecular characteristics of the region of the ventral pallium that leads to severe morphological malformation in the basolateral cortex (Stoykova et al., 2000
; Toresson et al., 2000
; Yun et al., 2001
) (Fig. 1C
). We used a Pax6/LacZ KO mouse, in which the endogenous Pax6 expression is reflected by ß-galactosidase activity (St Onge et al., 1997
), to study the consequences of the loss of Pax6 function on thalamocortical and corticofugal axon pathfinding. In Pax6 heterozygote brains, we correlated the Pax6 expression pattern to the different steps of thalamocortical development during the period E14.518.5. Carbocyanine dye tracing in Pax6 HT and Pax6 wild-type brains revealed that, corticofugal and thalamocortical axons temporarily arrest their growth at E14.5 at the border of the ß-galactosidase-positive region at the PSPB before they continue towards their targets. However, in Pax6 KO embryos, corticofugal and thalamocortical were unable to encounter each other at the PSPB and reach their final targets. Instead of crossing this boundary, they tended to descend into the ventral pallium in large aberrant fascicles (Fig. 1C
). In addition, cells normally situated in the ventral thalamus and internal capsule, were displaced into the hypothalamus and ventral pallium. These pathfinding defects were confirmed by immunohistochemistry for L1 and TAG-1, markers of the early axonal connections. The aberrant development of axonal connections in absence of Pax6 function appear to be related with ultrastructural defects of cells along the PSPB, as well as to a failure of axonal guidance molecule expression, including Sema3C, Sema5A and possibly Netrin-1 (Jones et al., 2002
).
Initial Thalamocortical Topography in Mutants (Including Reeler, L1 and Emx2) where Thalamic Axons Reach the Cortex Via an Altered Route
Reeler
The selective fasciculation of thalamic and preplate projections was proposed as a mechanism for thalamic afferents to traverse the internal capsule and advance to the cortex (Molnár and Blakemore, 1995). The unique pattern of thalamic fiber ordering in reeler mice supports this notion. In this mutant, the cortical plate develops below the early-generated preplate cells and therefore separates the incoming thalamic fibers from their target cells now located in a superplate (Caviness and Rakic, 1978
). The embryonic cortical plate is thought to be a nonpermissive environment for thalamic fiber ingrowth (Götz et al., 1992
). The existence of privileged pathways for axon growth could explain how thalamic axons in reeler are able to penetrate the cortical plate and steer up to reach the equivalent cells in the superplate, whilst ignoring the hostile territory of cortical plate cells around them (Molnár et al., 1998b
). Thalamic projections follow the same pattern of development observed in wild-type rodents, but in relation to the displaced superplate cells. Thalamic projections loop up to the superplate before they descend and branch and arborize in the cortical plate. We investigated how this altered thalamic input established periphery-related pattern and cytoarchitecture in the primary somatosensory cortex (S1).
Nissl sections of the mutant mice did not show clearly defined barrel boundaries, but CO staining revealed normal periphery-related pattern in a region corresponding to S1 (Polleux et al., 1998; Bronchti et al., 1999b
). This suggests that in reeler the majority of the thalamic fibers assume normal periphery-related pattern in the barrel cortex, but the cell patterning in the barrel field might be impaired. We examined the DG uptake after clipping all the mystacial whiskers with the exception of the three caudal-most of rows B and D. DG uptake examined on the coronal plane, revealed a columnar activation pattern with a highest DG uptake in the intermediate layers. This however was not confined to the upper part of the column, rather, showing a more diffuse activation pattern. In the tangential plane, DG uptake showed that the cortical activation pattern, and thus the areal distribution of whisker representation in reeler, is organized in an identical manner to that in normal mice (Bronchti et al., 1999b
). The abnormal trajectory to the cortex in the reeler does not seem to alter the ordered functional whisker representation.
L1 KO
The molecular mechanisms of contact guidance between thalamocortical and corticothalamic projections throughout the internal capsule are not known. Subplate neurons express immunoreactivity to the surface molecules L1 and TAG1 (Godfraind et al., 1988; Denaxa et al., 2001
) and fibronectin (Stewart and Pearlman, 1987
), which could provide highly attractive substrates for the growth of thalamic axons in an otherwise relatively non-permissive environment. A mouse deficient for L1 was produced (Cohen et al., 1997
), hence we were interested in examining the thalamocortical pathfinding and topography in this mutant. Our carbocyanine dye tracing experiments in embryonic and early postnatal L1 KO mouse brains revealed that fasciculation problems occur at the PSPB (Molnár et al., 1999
). Thalamic fibers gather in larger fiber bundles in the striatum and their path is different from the ones observed in normal mice. In spite of this abnormality thalamic fibers reach the cortex, and DiI crystal placement in embryonic and early postnatal animals reveals backlabeled thalamic cells and thalamic fibers with normal gross topography. Nissl sections of the mutant mice show clearly defined barrel boundaries and CO staining reveals normal periphery-related pattern in a region corresponding to SI primary somatosensory cortex. This suggests that the majority of the thalamic fibers branch and arborize normally and assume periphery-related pattern in the barrel cortex (Molnár et al., 1999
). We used DG mapping in combination with Nissl and CO staining to examine whether or not a functional cortical representation of the mystacial whiskers can be related to a cytoarchitectonic organization in the mutant. The stimulation of the three caudal-most whiskers of rows B and D during active exploration of a stimulus-rich cage results in a normal pattern of cortical distribution both on coronal and tangential planes. Thus, a modified organization of fiber fascicles in the internal capsule of the L1 KO mice does not seem to alter the ordered, functional whisker representation.
Evidence for Early Thalamocortical Transmission in the Cerebral Cortex
It was demonstrated that the peripheral sensory organs already generate spontaneous activity patterns at ages (Galli and Maffei, 1988; Meister et al., 1991
) when the sensory afferents begin to reach the thalamus. These activity patterns could elicit EPSPs on thalamic projecting neurons (Mooney et al., 1996
) which are capable of relaying them to cortex (Friauf and Shatz, 1991
), and thus these activity patterns may alter the forming terminals within the subplate and cortical plate by controlling side branch formation.
To gain an insight into the formation of early thalamocortical synapses, we recorded optical images, using voltage sensitive dyes, in the cerebral cortex of prenatal rats by selective thalamic stimulation (Higashi et al., 2002) of thalamocortical slice preparations (Agmon et al., 1993
). The embryonic developmental pattern in rat is similar to that in mice, but in rat the developmental stage is
1 day less advanced. At E17, thalamic stimulation elicits excitation that rapidly propagates through the internal capsule to the cortex. These responses last <<1015 ms, and are not affected by the application of glutamate receptor antagonists, suggesting they might reflect presynaptic fiber responses (Fig. 2A
13). At E18, long-lasting (>>300 ms) responses appear in the internal capsule. These responses are abolished by perfusion of glutamate receptor antagonists, which indicates synapse-mediated activation of internal capsule cells (Fig. 2B
13). At E19, distinct long-lasting responses appears mainly in the cortical subplate (Fig. 2C
). By E21, shortly before birth, the deep cortical layers are also activated in addition to the subplate. The laminar location of the responses was determined in the same slices by Nissl-staining or birthdating with bromodeoxyuridine (BrdU) at E13 (Higashi et al., 2002
). Our results demonstrate that there is a delay of several days between the arrival of thalamocortical axons at the subplate at E16 and the appearance of functional thalamocortical synaptic transmission at E19. Since thalamocortical connections are already functional within subplate and in deep cortical plate at embryonic ages, prenatal thalamocortical synaptic connections could influence cortical circuit formation before birth.
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There are various forms of neurotransmitter release, which could activate recipient cells. Most synaptic vesicle release occurs from nerve terminals after they have been triggered by action potentials. The spontaneous vesicle release is not regulated and the paracrine type, non-vesicular release, does not require synaptic vesicle fusion mechanisms (Rizo and Südhof, 2002).
Snap25 KO
Disruption of the gene encoding SNAP25, a component of the SNARE complex required for regulated neuroexocytosis, eliminates evoked but not spontaneous neurotransmitter release (Washbourne et al., 2002). The Snap25 null mutant mouse provides an opportunity to test whether synaptic activity is required for prenatal neural development. We find that evoked release is not needed for at least the gross formation of the embryonic forebrain, since the major features of the diencephalon and telencephalon are normal in the null mutant mouse. Tracing of the thalamocortical fiber pathway reveals normal growth kinetics and fasciculation patterns between E17.5 and E19. As in normal mice, thalamocortical axons of the mutant reach the cortex, accumulate below the cortical plate, and then start to extend side-branches in the subplate and deep cortical plate (Fig. 3A,B
). Multiple carbocyanine dye placements in the cortical convexity reveals a normal overall topography of both early thalamocortical and corticofugal projections (Fig. 3C,D
) (Molnár et al., 2002). Unfortunately the mutants die at birth and thus, the period of thalamic axon branching and termination in layer 4 and the barrel formation remain out of our reach.
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Discussion |
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Aberrant Early Pioneer Projections from Internal Capsule Cells Are Associated with Axon Growth Defects at the DiencephalicTelencephalic Boundary
In Mash1 homozygous mice, the internal capsule cells with thalamic projections are missing and thalamocortical axons fail to enter the internal capsule (Tuttle et al., 1999). Impairment in the early growth of thalamic axons has also been reported in Sema6A KO brains (Leighton et al., 2001
). In Emx2 homozygous mice, the early internal capsule projections take an aberrant ventral route at the diencephalictelencephalic boundary, and some of the thalamocortical axons follow them as they traverse that region (López-Bendito et al., 2002
). The interaction between thalamic and corticofugal projections is more of a low five rather than handshake in the Emx2 KO. Both sets of projections get derailed ventrally, both cross the diencephalon in an aberrant pattern.
In Pax6 KO mice, it was observed that if the internal capsule cell projections to thalamus are aberrant, then the thalamic projections also take this aberrant path. It is known that the diencephalictelencephalic junction zone is compromised in Mash1, Emx2 and Sema6A mutants, but the causal relationship between these events is not understood. The pattern in Mash1, Emx2 and Pax6 KO mice is compatible with the suggestion that ventral thalamic, and internal capsule cells and their projections, guide the outgrowth of thalamic projections. This hypothesis will have to be abandoned if normal thalamic projections are described in the absence of these pioneering pathways, or, if aberrant thalamic development not accompanied by the aberrant development of the thalamic projections occurs at this segment.
Disrupted Thalamocortical Development at the Striatocortical Junction Is Accompanied by Anomalous Corticofugal Projections
The second common theme emerging from recent studies on mutants is that both thalamocortical and corticothalamic projections are disrupted at the striatocortical junction (Hevner et al., 2001, 2002
; Jones et al., 2002
). It is surprising how many homeobox related genes can alter thalamic development at the PSPB, which appears as a rather vulnerable region following modifications in gene expression. Synchronized choreography of thalamocortical development and forebrain regionalization is needed for the successful completion of the hurdle to cross this region. Any spatial/temporal misalignment can have dramatic effects. Errors occurring in corticothalamic and thalamocortical pathfinding within the region of the internal capsule were described in mice with mutations of transcription factor genes expressed in cortex (Tbr1), thalamus (Gbx2), or in both (Pax6) (Kawano et al., 1999
; Miyashita-Lin et al., 1999
; Hevner et al., 2001
, 2002
). In the Pax6/LacZ mutant, for example, the majority of corticofugal fibers do not turn from cortex to the internal capsule, instead they continue to descend to ventral pallium. The thalamocortical fibers fail to enter the cortex, and the lateral pallial sector is morphologically compromised (Stoykova et al., 2000
; Jones et al., 2002
). We consider the aberrant fiber growth pattern observed in Pax6 KO only as limited support for the handshake hypothesis, since the phenotype is rather complicated (Fig. 1C
). There are numerous mutants [Tbr1, Gbx2, see Hevner et al. (Hevner et al., 2002
)] with much less severe abnormalities at this region; nevertheless thalamic fibers fail to cross. It is puzzling that the gene expression is localized proximal or distal to the site of the actual guidance defect at the striatocortical junction. It is conceivable that an intact expression of certain receptors or surface molecules is required by both sets of projections to react to guidance signals in the region. A better understanding of the interaction between gene expression and environmental factors is needed at different sectors of the fiber trajectories.
Map Formation in the Cortex after Altered Thalamocortical Deployment
A significant fraction of thalamic projections in Emx2 KO mice is misrouted at the diencephalictelencephalic boundary and this abnormality is associated with displaced projections of internal capsule cells and disrupted entorhinal and perirhinal cortical projections. As we discuss above, it appears that most of these misrouted thalamocortical projections recovered and ascended from the ventral telencephalon towards different cortical regions. The misrouting caused a considerable delay in thalamic fibers arriving to the cortex, which might contribute to the altered cortical topography. The abnormalities likely to be related to earlier guidance defects, some of which are located at the diencephalictelencephalic boundary where Emx2 has strong expression during development. Although this thalamic axon guidance defect is linked with the altered Emx2 expression pattern in the dorsal cortex and with aberrant growth of some of the early corticofugal projections at the striatocortical junction, it most probably occurs independently from the cortical Emx2 expression. Similar abnormalities were found in the Sema6A mutant mouse (Leighton et al., 2001), and Sema6A might be one of the candidate genes responsible for some of the abnormalities observed in Emx2 mutants.
It seems that a precise trajectory might not be crucial for the final pattern of cortical targeting. L1, reeler mice provide examples for cases where thalamic projections arrive to the cortex through aberrant routes, yet they form a normal periphery-related pattern in the primary somatosensory cortex. It will be interesting to further study these interesting paradigms in mutants during their postnatal development. The challenge is to dissect the role of the gene expression patterns en route to the cortex and within the cortex itself.
Axonal Pathfinding and Cortical Regionalization Defects Might Be Independent
There is a continuing debate as to how the developing pallium influences thalamocortical development, and in turn whether thalamocortical afferents affect the development of the cortex. Early gene expression patterns are normal in the absence of thalamic input during embryonic life (Nakagawa et al., 1999; Miyashita-Lin et al., 1999
). It has been demonstrated that there is a shift in the areal identity in the cerebral cortex of Emx2 and Pax6Sey/Sey mutant mice, which is matched with altered distribution of thalamocortical projections in the Emx2 KO brains (Bishop et al., 2000
; Mallamaci et al., 2000
). In the Pax6 KO brains, no thalamic projections reach the cortex, suggesting that the shift in cortical representation observed in the Pax6 KO cortex might, in fact, be independent from thalamic axon targeting and does not rely on the presence or absence of thalamic projections. Our tracing studies demonstrated that in both Emx2 KO (López-Bendito et al., 2002
) and Pax6 KO mice (Jones et al., 2002
), a large proportion or the entire thalamocortical axon population was misrouted at the border between the diencephalon and telencephalon. In addition, in the Pax6 KO an additional defect prevented the thalamic afferents from invading the cortex through the striatocortical boundary. It will be exciting to investigate the formation of cortical areas in mutants with axonal targeting abnormalities, but without primary cortical alterations. Will the thalamic projections compensate for their targeting error, or they shift the cortical representation?
What Form of Intercellular Communication Is Needed for the Remodeling of the Initial Thalamocortical Map?
In contrast with the initial gross deployment of thalamocortical and corticothalamic connections, the remodeling of cortical circuitry during thalamic fiber invasion is probably a more complex process in which patterns of afferent and local activity, expression of surface molecules and growth factors, and cell death all play crucial roles (Katz and Shatz, 1996). In turn, the remodeling may lead to the formation of new synapses and therefore to new distributions of activity. Early thalamic projections are capable of eliciting sustained depolarization patterns in the subplate at the time of side-branch formation (Friauf and Shatz, 1991
; Higashi et al., 2002
; Molnár et al., 2003). This early interaction is different from the mature postnatal form, being relatively smaller, but much longer. Our data in Snap25 KO mice suggest that axonal growth and early topographic arrangement of these fiber pathways do not rely on activity-dependent mechanisms requiring evoked neurotransmitter release. We propose that other forms of intercellular communication might still play a part. There are three forms of neurotransmitter release, which could activate recipient cells: (i) regulated synaptic vesicle release, which is absent in Snap25 KO; (ii) spontaneous vesicle release, which is absent in Munc13 and Munc18 KO mice; and (iii) paracrine type, non-vesicular release, which is still present in Munc18 and 13 KO. With these currently available mutants it should be possible to create various in vivo and in vitro paradigms to determine which mechanisms are required for different periods of cortical and thalamocortical development. In these experiments, neuronal interactions will have to be better defined, since it is no longer sufficient to determine whether developing neurons play a melody or not; it will be necessary to define what melody and whether they sing, hum or just whisper it.
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Conclusion |
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Acknowledgments |
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References |
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