interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal...

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Schizophrenia Research

Interstitial white matter neuron density in the dorsolateral prefrontal

cortex and parahippocampal gyrus in schizophrenia

S.L. Eastwood *, P.J. Harrison

University of Oxford, Department of Psychiatry, Neurosciences Building, Warneford Hospital, Oxford OX3 7JX, UK

Received 31 May 2005; received in revised form 30 June 2005; accepted 3 July 2005

Available online 1 August 2005

Abstract

Alterations in the density or distribution of interstitial white matter neurons are taken as evidence in support of an early

developmental component to schizophrenia. However, the existence and nature of interstitial white matter neuron changes in

schizophrenia remain inconclusive. Recently, we reported that interstitial white matter neuron density is increased in the

superficial white matter of the superior temporal gyrus in schizophrenia, but unchanged in deep white matter. This study extends

our investigations to the dorsolateral prefrontal cortex and parahippocampal gyrus. Using the specific neuronal antibody NeuN,

interstitial white matter neuron density was found to be increased in schizophrenia in the superficial white matter of the

dorsolateral prefrontal cortex, with no significant changes elsewhere. As interstitial white matter neurons are presumed to be

remnants of the embryonic cortical subplate, these findings provide additional evidence supportive of an early developmental

abnormality in schizophrenia.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Hippocampal formation; Immunohistochemistry; NeuN; Neurodevelopment; Postmortem; Subplate

1. Introduction from a range of epidemiological, imaging, and clinical

That schizophrenia is a neurodevelopmental dis-

order (Lewis and Levitt, 2002; Weinberger, 1987)

leading to abnormal synaptic connectivity (Frankle et

al., 2003; Harrison, 1999) has become the prevailing

pathogenic hypothesis. Support for an early develop-

mental component to schizophrenia comes not only

0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.schres.2005.07.001

* Corresponding author. Tel.: +44 1865 223620; fax: +44 1865

251076.

E-mail address: [email protected]

(S.L. Eastwood).

data, but also from the nature of neuropathological

changes observed in the disorder (Harrison, 1997;

Lewis and Levitt, 2002). Of these, alterations in the

density and/or position of neurons, in combination

with an absence of evidence for neurodegenerative

processes (see Harrison, 1999), have been widely con-

sidered to lend credence to the neurodevelopmental

model of schizophrenia. In particular, interstitial white

matter neurons (IWMNs) have been the focus of sev-

eral studies, and changes in this neuronal population in

schizophrenia interpreted as morphological evidence

in support of an early developmental anomaly.

79 (2005) 181–188

S.L. Eastwood, P.J. Harrison / Schizophrenia Research 79 (2005) 181–188182

IWMNs are thought to represent the relatively few

adult remnants of the subplate (Chun and Shatz,

1989), an embryonic structure important in cortico-

genesis, neuronal migration, and the formation of

corticothalamic and thalamocortical connections

(Allendoerfer and Shatz, 1994; Kanold et al., 2003).

Hence, changes in IWMN density and/or distribution,

reported in several brain regions in schizophrenia

(Akbarian et al., 1993a,b, 1996; Anderson et al.,

1996; Eastwood and Harrison, 2003; Kirkpatrick et

al., 1999, 2003; Rioux et al., 2003), are considered

indicative of a subplate abnormality (either in terms of

survival of subplate neurons, or their migration) which

can only have taken place during early development.

As circuits formed by subplate neurons are essential in

the selective remodeling of thalamocortical excitatory

synaptic connections, and in the maturation of cortical

neurons (Allendoerfer and Shatz, 1994; Kanold et al.,

2003; Kanold, 2004), such a subplate abnormality

could contribute to the aberrant connectivity described

in schizophrenia. However, the nature of IWMN

changes in schizophrenia, and thus their interpreta-

tion, remains unclear (see Eastwood and Harrison,

2003 for review). There is some agreement across

the literature that changes in IWMN density are in

Table 1

Summary of the main findings of previous studies of interstitial white ma

Brain

regionaSample

sizebNeuronal

stainc

Akbarian et al., 1993a. DPFC 5:5 NAPDH

Anderson et al., 1996. DPFC 5:5 MAP2

Beasley et al., 2002. DPFC 15:15 MAP2

Kirkpatrick et al., 2003. DPFC 5:7d MAP2

Akbarian et al., 1993b. MTG 7:7 NAPDH

Eastwood and Harrison, 2003. STG 12:12 NeuN

Kirkpatrick et al., 1999. IPC 9:9d MAP2

Akbarian et al., 1993b. HF 7:7 NAPDH

Akbarian et al., 1996. DPFC 20:20 NAPDH, MAP2

and SMI-32

Rioux et al., 2003. PHG 15:41 MAP2

a DPFC: dorsolateral prefrontal cortex; IPC: inferior parietal cortex; M

superior temporal gyrus.b Number of control subjects:subjects with schizophrenia.c NeuN: anti-neuronal nuclei; MAP2: anti-microtuble associated protein

ase; SMI-32: anti-SMI-32.d Subjects with schizophrenia split into deficit and nondeficit subgroupse Significant in the deficit subgroup only.f Changes in IWMN density were only detected in the pre- and parasubic

formation examined.

either superficial or deep subcortical white matter

(summarized in Table 1), with intermediate compart-

ments giving negative or equivocal results. However,

there is little consensus beyond this point. For exam-

ple, while Akbarian and colleagues (Akbarian et al.,

1993a, 1996) found an increased IWMN density in

the deep versus the superficial white matter of the

dorsolateral prefrontal cortex (DPFC), the opposite

pattern of change (Anderson et al., 1996) and no

difference (Beasley et al., 2002) in this region have

also been reported. The inconsistency in the data

suggests that further examination of IWMNs in schi-

zophrenia is warranted. Our initial study focused on

the superior temporal gyrus (Eastwood and Harrison,

2003). The current study extends our investigation to

the DPFC and the parahippocampal gyrus (PHG).

2. Materials and methods

2.1. Subjects studied

The demographic details are summarised in Table 2.

Tissue from the DPFC and PHG was available from an

overlapping subset of subjects as described (Eastwood

tter neurons in schizophrenia

Superficial white matter Deep white matter

Decreased Increased

Increased Unchanged

Unchanged Unchanged

Increasede Not examined

Unchanged Increased

Increased Unchanged

Increasede Not examined

Decreasedf Unchanged

Interstitial white matter neuron distribution in schizophrenia

Altered distribution. Did not directly compare IWMN density.

No change in IWMN density but altered IWMN distribution.

TG: middle temporal gyrus; PHG: parahippocampal gyrus; STG:

2; NAPDH: nicotinamide–adenine dinucleotide phosphate-diaphor-

.

ulum in schizophrenia, and unchanged in the rest of the hippocampal

Table 2

Demographics of subjects included in the study

Dorsolateral prefrontal cortex Controls

(n =12)

Schizophrenics

(n =11)

Gender 5 M, 7 F 6 M, 5 F

Age (years) 56F19 52F18

Range 22–79 19–71

Brain pH 6.59F0.20 6.45F0.25

Range 6.20–6.76 6.05–6.72

Post mortem interval (hours) 38F16 43F19

Range 19–72 18–76

Onset of psychosis (years) – 28.0F9.5

Range – 14–47

Duration of illness (years) – 24.4F15.8

Range – 5–53

Hippocampal formation Controls

(n =12)

Schizophrenics

(n =13)

Gender 8 M, 4 F 8 M, 5 F

Age (years) 61F18 55F19

Range 22–83 19–83

Brain pH 6.52F0.21 6.39F0.27

Range 6.20–6.74 6.03–6.72

Post mortem interval (hours) 33F13 44F18

Range 19–65 18–76

Onset of psychosis (years) – 27.9F8.7

Range – 14–47

Duration of illness (years) – 27.1F17.0

Range – 5–57

Values are meanFSD. Tissue from both regions was available from

8 of the control subjects and 11 subjects with schizophrenia.

S.L. Eastwood, P.J. Harrison / Schizophrenia Research 79 (2005) 181–188 183

and Harrison, 2005). The research on this brain series is

approved by the Oxfordshire Psychiatric Research

Ethics Committee, and retention of the tissue follows

current British guidelines.

Blocks were dissected from the middle third of the

middle frontal gyrus (Brodman area 9/46) and the

mid-body of the hippocampal formation including

the PHG. Frozen sections (18 Am) were collected

onto gelatin-coated slides, and returned to �80 8C.All material was coded, and experiments and analyses

conducted blind to diagnosis.

2.2. NeuN immunocytochemistry

The anti-neuronal nuclei (NeuN) monoclonal anti-

body, a widely used neuronal marker which works

well in post mortem tissue, was chosen to identify

IWMNs (Lind et al., 2005). NeuN immunohisto-

chemistry was carried out as described (Eastwood

and Harrison, 2003). Briefly, duplicate sections

from each subject and each region were fixed in

4% paraformaldehyde for 5 min, followed by a 30

min incubation in 3% hydrogen peroxide in metha-

nol. After 3 brief washes in phosphate buffered saline

(PBS), non-specific binding sites were blocked with

10% normal horse serum in PBS containing 0.3%

Triton X-100 (PBS-T; 30 min). Sections were incu-

bated overnight at 4 8C with NeuN antibody, diluted

1 :100 with PBS-T containing 1% normal horse

serum and visualised using an ABC Elite kit (Vector

Laboratories, Peterborough, UK) and diaminobenzi-

dine. All subjects were included in a single experi-

mental run, alongside negative control sections in

which the primary antibody was omitted.

2.3. Measurement of NeuN-labelled interstitial white

matter neurons

IWMN density was measured as described for our

study of this neuronal population in the superior

temporal gyrus (Eastwood and Harrison, 2003).

Briefly, IWMNs were counted in two sampling

dbinsT or compartments. For DPFC, these were

placed in the middle of the straight part of the sulcal

bank, whilst for the PHG, bins were placed within

the white matter bordered by the straight part of

CA1/subiculum opposing the straight part of the

gyrus (see Fig. 1). The location was chosen to

avoid problems of curvature and to facilitate demar-

cation of the bbottomQ of the white matter (defined

as half of the distance to the grey/white matter

border of the facing sulcal bank). For both brain

regions, the first sampling bin, called dsuperficialT,was immediately below the point at which the white

matter was unequivocally identifiable based on the

rapid, steep decline in neuronal density from the

overlying layer VI. The second compartment, called

ddeepT, was placed in the bottom third of the white

matter. Within each bin, 20 counting boxes of

dimensions 0.47�0.47 mm (0.23 mm2) were ran-

domly placed. Using the �20 objective, all NeuN-

stained IWMNs within each box were counted,

except those touching the left and top sides. For

the DPFC, an average of 198 (range 139–313) super-

ficial IWMNs, and 40 (range 16–100) deep IWMNs,

and for the PHG, an average of 106 (range 48–165)

superficial IWMNs, and 38 (range 5–78) deep

Fig. 1. Cartoon of the (A) hippocampal formation and (B) dorso-

lateral prefrontal cortex demonstrating the location of the white

matter regions sampled. (C) Enlargement of the boxed region in

(B). The two boxes represent the position from which superficial

and deep IWMNs were sampled.


IWMNs, were counted. Test–retest variation in

IWMN density measures was 2%.

To help ensure that any differences in IWMN

density observed in schizophrenia were not due to

inadvertent misplacing of the grey–white matter bor-

der, or confounded by a group difference in white

matter depth, we measured grey matter and white

matter depths, and parahippocampal white matter

area, using the same borders defined above.

2.4. Statistical analyses

Comparisons of IWMN density between cases

and controls were made by analysis of variance

(ANOVA). Correlations with potential confounders,

and with clinical variables, were investigated using

the Spearman coefficient. In addition, correlations

were also run for IWMN densities in superficial

versus deep white matter. All tests were two-tailed,

with P=0.05 being considered significant. One

secondary comparison was planned, based on our

earlier study which suggested that increased super-

ficial IWMN density occurred mainly in patients

with negative symptoms (Eastwood and Harrison,

2003).

3. Results

IWMNs stained in the DPFC and PHG with NeuN were

mainly bipolar or multipolar neurons with horizontally or

variably orientated dendrites, and were similar in appearance

to those identified in the superior temporal gyrus (Eastwood

and Harrison, 2003), and in the DPFC and hippocampal

formation using other markers (Akbarian et al., 1993a,b,

1996; Anderson et al., 1996; Kirkpatrick et al., 1999). For

both regions, a marked gradient in IWMN distribution was

observed, with the highest density of IWMNs immediately

adjacent to the grey matter, and fewest IWMNs in the deep

white matter.

The results are shown in Fig. 2. For both the DPFC and

PHG, no changes in the density of IWMNs in the deep white

matter were detected in schizophrenia. A significant increase

in IWMN density was detected in schizophrenia in the

superficial white matter of the DPFC (F1,21=8.41,

p =0.009; Fig. 2a), but not in the PHG (F1,22=1.33,

p =0.262; Fig. 2b). No significant correlations of IWMN

density were detected between superficial and deep white

matter in controls or subjects with schizophrenia. IWMN

density did not correlate with age of onset or disease dura-

tion. Neither did it correlate with age at death, PMI or brain

pH, and the inclusion of these potential confounders as

covariates in the analyses did not alter the results. No

significant differences in the depth of the white matter

were detected, although DPFC white matter depth trended

towards an increase in schizophrenia (Table 2). IWMN

density did not correlate with white matter or grey matter

depth. No differences were found between patients with

0

10

20

30

40

50

60

70

80 *

Superficial IWMNs Deep IWMNs

Neu

rons

/mm

2

0

10

20

30

40

Superficial IWMNs Deep IWMNs

Neu

rons

/mm

2

A

B

Fig. 2. Density of IWMNs in superficial (solid symbols) and deep

(open symbols) white matter of (A) dorsolateral prefrontal cortex

and (B) parahippocampal gyrus in controls (circles) and subjects

with schizophrenia (triangles). *F1, 21=8.41, p =0.009, ANOVA.


(n =4) and without (n =4) negative symptoms (data not

shown).

Table 3

Summary of morphometric results in the dorsolateral prefronta

cortex and parahippocampal gyrus of control subjects and subjects

with schizophrenia

Controls Schizophrenics

Dorsolateral prefrontal cortex

Grey matter depth (lm) 2582F316 3014F565a

White matter depth (lm) 1332F393 1725F564

Parahippocampal Gyrus

Grey matter depth (lm) 3151F533 2852F335

White matter depth (lm) 1021F260 946F212

White matter area (mm2) 70.6F12.0 72.8F11.4

Values are meanFSD.a Effect of diagnosis (F1,19=4.54, p=0.046, ANOVA). Measure

ments were not taken from one control subject and one subject with

schizophrenia due to ice crystal damage to the superficial grey

matter.

4. Discussion

The main finding of this study is that IWMN

density in DPFC superficial white matter is increased

in schizophrenia, with no change detected in the deep

white matter. No significant differences in IWMN

density were found in the PHG, though a similar

trend was observed with IWMN density tending to

be higher in schizophrenia in the superficial white

matter. Given the premise that changes in IWMNs

implicate early developmental events (see Eastwood

and Harrison, 2003), these data provide additional

evidence supportive of schizophrenia as a neurodeve-

lopmental disorder.

Before commenting on the results further, one

methodological limitation of the study should be

noted. As we used conventional two-dimensional

counting methods, no comment can be made as to

whether increased IWMN density implies an alteration

in their numbers in schizophrenia, and it is possible

that the data may have been influenced by changes in

the area of the regions sampled, For this reason, grey

and white matter depths, and parahippocampal white

matter area, were measured (Table 3), but no correla-

tions were detected between these values and IWMN

density in either the DPFC or the PHG. Moreover,

white matter depth of the DPFC was slightly increased

in the schizophrenia group (Table 3), which would

tend to decrease superficial IWMN density rather

than increase it. As the depth of the grey matter was

also increased (Table 3), altered superficial IWMN

density (which was always sampled slightly away

from the grey/white matter border) is not thought to

be due to the accidental inclusion of layer VI neurons.

Together with the finding that deep IWMN density in

the DPFC is unchanged, and that the current findings

are of a similar value and direction of change as those

of an earlier study (Anderson et al., 1996), the data

suggest that increased superficial IWMN density in the

DPFC in schizophrenia is a genuine finding.

4.1. IWMN changes in schizophrenia

This study strengthens the evidence that there are

IWMN abnormalities in schizophrenia. Using the

l

-


same sampling strategy and staining method to iden-

tify IWMN as employed in our study of the superior

temporal gyrus (Eastwood and Harrison, 2003), our

finding of increased IWMN density in the superficial

white matter in schizophrenia was replicated in the

DPFC (Fig. 2). Although many of the subjects exam-

ined in the current study were also included in our

study of the superior temporal gyrus, IWMN density

did not correlate in controls or subjects with schizo-

phrenia between the different brain areas examined

(all rb0.21, p N0.37), and hence group differences in

the two areas are not being driven by the same

individuals. The greater variance in IWMN data in

the PHG means that a larger brain series is needed to

determine if IWMN density in this area is or is not

unaffected in schizophrenia. In this respect it is of

note that in the original IWMN studies conducted by

Akbarian and colleagues (see Table 1), IWMN

changes were detected in the superior temporal

gyrus and DPFC, with IWMN density in the hippo-

campal formation being mostly unchanged (Akbarian

et al., 1993a,b). A recent large study (Rioux et al.,

2003) suggests that the distribution of IWMNs in the

PHG may be altered in schizophrenia, but given

differences in the sampling methodologies, these

results are not directly comparable to the current

data.

Although our finding of increased superfical

IWMN density in the DPFC is consistent with our

earlier study of the superior temporal gyrus, and with

that of others in the DPFC (Anderson et al., 1996;

Kirkpatrick et al., 2003; see Table 1), it is discrepant

with the results of the original studies by Akbarian et

al. (1993a,b, 1996). A closer examination of the sam-

pling strategies suggests one potential explanation. In

our study, IWMN density was sampled from the mid-

dle of the bank (or side) of the sulcus. The diagram and

explanation given by Anderson et al. (see Fig. 1 in

Anderson et al., 1996) suggests that this was also the

location examined in their study, whilst Akbarian and

colleagues appear to have also sampled from around

the sulcal fundus (see Fig. 1 in Akbarian et al., 1996).

As cortical depth and cell density measures vary

around sulci (Chance et al., 2004), as can neuronal

immunoreactivity (Sisodiya et al., 2000), IWMN den-

sities may also differ depending on the sulcogyral

position sampled. To examine this possibility, we

resampled IWMN density in the superficial white

matter of the DPFC from the 3 control subjects and

4 subjects with schizophrenia for whom sections con-

tained both the middle of the sulcal bank, and the

complete fundus. This subgroup was representative

of the main study, in that an increase was found in

schizophrenia when IWMN density was sampled from

the bank of the sulcus. In contrast, no difference (nor

trend) between controls and schizophrenics in this

subgroup was found when superficial IWMN density

was sampled from beneath the fundus (data not

shown). As this subgroup was small, these pilot data

were not included in our main study, nor statistically

analyzed, and should be treated with caution. Never-

theless, they suggest that sulcogyral sampling strategy

should be taken into account when interpreting IWMN

findings reported in schizophrenia. Despite the con-

tinuing uncertainties, Table 1 and the current study

together mean that five out of six studies report

changes in DPFC IWMNs in schizophrenia. Hence,

although the nature of IWMN changes in schizophre-

nia differ between studies (possibly due to sampling

differences as discussed above), the finding that

IWMN density is altered in schizophrenia represents

a relatively robust neuropathological finding.

4.2. IWMN alterations and the pathophysiology of

schizophrenia?

Changes in IWMN density and/or distribution are

interpreted as indicative of aberrant neurodevelop-

ment, most often as a manifestation of a subplate

anomaly. This suggestion has been extensively dis-

cussed (and will not be reiterated here), but little

comment has been made as to which genetic and/or

environmental factors may contribute to such an

anomaly. One interesting finding, which may be of

relevance, hints towards a possible environmental

influence. The density of nicotinamide–adenine dinu-

cleotide phosphate-diaphorase (NAPDH) neurons is

increased in the white matter in a rat model of mal-

nutrition and/or low birth weight (Rocha de Melo et

al., 2004). In rats, the first three weeks of postnatal life

corresponds to the period of maximal subplate cell

loss (see Arias et al., 2002), and it is tempting to

speculate that malnutrition and/or low birth weight,

both implicated in schizophrenia (Cannon et al.,

2002a,b; Hoek et al., 1998; Hulshoff Pol et al.,

2000; Susser et al., 1996), may affect IWMN survival.


Regardless, the findings of Rocha de Melo et al.

(2004) provide an empirical precedent for the assump-

tion that IWMN changes in schizophrenia have an

early developmental origin. That superficial IWMN

density is increased in the heterozygous reeler mouse

(Tueting et al., 1999) suggests that there may also be

genetic influences upon subplate survival.

There is a considerable phenotypical heterogeneity

of IWMNs (Arias et al., 2002; Meyer et al., 1992;

Smiley et al., 1998). As we used a common neuronal

marker, NeuN, we do not know if one or other sub-

populations are differentially affected. In turn, it is

difficult to predict the functional correlates of an

increased density of superficial DPFC IWMNs in

schizophrenia. Future studies using more specific

markers may be able to answer this question, and

provide clues that may lead towards a better under-

standing of the cell types involved, and thence the

pathophysiological consequences.

Acknowledgements

SLE was recipient of the Margaret Temple

Research Fellowship of the British Medical Associa-

tion. Additional support was provided by the Well-

come Trust, and by a Centre Award from the Stanley

Medical Research Institute.

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interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal...

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